Physiol Rev 88: 841– 886, 2008;
doi:10.1152/physrev.00035.2007.
Evolution and Function of the ADP Ribosyl Cyclase/CD38 Gene
Family in Physiology and Pathology
FABIO MALAVASI, SILVIA DEAGLIO, ADA FUNARO, ENZA FERRERO, ALBERTO L. HORENSTEIN,
ERIKA ORTOLAN, TIZIANA VAISITTI, AND SEMRA AYDIN
Laboratory of Immunogenetics, Department of Genetics, Biology, and Biochemistry and Centro di Ricerca in
Medicina Sperimentale, University of Torino Medical School, Torino, Italy
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I. Introduction
II. Ontogeny and Tissue Distribution
A. Thymocytes and T lymphocytes
B. B lymphocytes
C. Myeloid lineage
D. Nonimmune tissues
E. CD157
III. CD38/CD157 Structure
A. CD38
B. CD157
IV. Receptorial Functions
A. Historical perspective
B. Evidence of a cell-bound ligand
C. Signaling in human models
D. Signaling in murine models
E. CD157
V. Enzymatic Activities
A. Historical perspective
B. Enzymatic activities controlled by CD38
C. Enzymatic activities controlled by CD157
D. Regulation of the enzymatic activities
D. Functional models
VI. Animal Models
VII. Phylogeny and Gene Organization
A. From one soluble gene to a family of transmembrane proteins
B. Structure and organization of CD38 and CD157 genes
VIII. Human Disease Models
A. Diabetes
B. HIV infection
C. Chronic lymphocytic leukemia
IX. Therapeutic Applications
A. CD38 as a constitutive target
B. De novo induced expression of CD38 for tumor targeting
C. CD38 as a target for gene therapy
X. Concluding Remarks
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Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S. Evolution and
Function of the ADP Ribosyl Cyclase/CD38 Gene Family in Physiology and Pathology. Physiol Rev 88: 841– 886, 2008;
doi:10.1152/physrev.00035.2007.—The membrane proteins CD38 and CD157 belong to an evolutionarily conserved
family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38
(and CD157) cleaves NAD⫹ and NADP⫹, generating cyclic ADP ribose (cADPR), NAADP, and ADPR. These reaction
products are essential for the regulation of intracellular Ca2⫹, the most ancient and universal cell signaling system.
The entire family of enzymes controls complex processes, including egg fertilization, cell activation and proliferation, muscle contraction, hormone secretion, and immune responses. Over the course of evolution, the molecules
have developed the ability to interact laterally and frontally with other surface proteins and have acquired
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0031-9333/08 $18.00 Copyright © 2008 the American Physiological Society
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MALAVASI ET AL.
receptor-like features. As detailed in this review, the loss of CD38 function is associated with impaired immune
responses, metabolic disturbances, and behavioral modifications in mice. CD38 is a powerful disease marker for
human leukemias and myelomas, is directly involved in the pathogenesis and outcome of human immunodeficiency
virus infection and chronic lymphocytic leukemia, and controls insulin release and the development of diabetes.
Here, the data concerning diseases are examined in view of potential clinical applications in diagnosis, prognosis,
and therapy. The concluding remarks try to frame all of the currently available information within a unified working
model that takes into account both the enzymatic and receptorial functions of the molecules.
I. INTRODUCTION
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The invitation from the Journal to write a review on
the human CD38 gene family was extended after the CD38
Meeting held in 2006 in Torino, Italy. This meeting was the
latest of what started as a series of mini-conventions
initially attended by a limited number of devotees and that
continues to attract a growing number of participating
scientists as new publications and citations fuel interest
in the molecule.
CD38 was identified by E. L. Reinherz and S. F.
Schlossman (Boston, MA) while conducting detailed analysis of the cell surface by means of monoclonal antibodies, as part of their pioneer search for molecules acting as
T-cell receptors and transducers of signals elicited by the
encounter with specific antigens. This work resulted in
the definition of a vast array of molecules, including some
involved in the economy of discrete subsets of cells (e.g.,
CD4 and CD8), some playing a more general role as
metabolic regulators (CD71/TFR-1), and several others,
such as CD38, serving as markers for the study of thymocytes, activated T cells, and selected tissues.
Our interest in investigating human CD38 was piqued
by its distribution, which was seen to range from discrete
expression during lymphocyte differentiation to an extremely limited presence during the normal physiological
life of both T and B cells. The molecule was reexpressed
at high density by cells undergoing activation and in selected leukemias. Furthermore, in apparent contrast to
the notion that CD38 acts merely as an activation marker,
terminally differentiated plasma cells and their pathological counterparts expressed the highest surface density
among human cells.
To study the function of the molecule, we took the
approach of raising several monoclonal antibodies specific for discrete epitopes of CD38 so as to identify their
contribution to the actual role played by the molecule.
Hon Cheung Lee, a biochemist working in unrelated
fields, came across CD38 while studying new intracellular
messengers in the sea mollusk Aplysia. During the course
of his work, he made the surprising finding of the striking
similarity between human CD38 and the enzyme ADP
ribosyl cyclase, purified from a mollusk predating Homo
sapiens by 700 million years.
This and other related observations confirmed that
ectoenzymes could no longer be considered oddities in
leukocyte biology; on the contrary, it was seen that ⬃3.5%
of the molecules expressed on the surface of human and
murine cells shared such enzymatic characteristics. This
finding galvanized the attention and interest of basic and
clinical scientists. Nucleotide-metabolizing ectoenzymes
constitute a subgroup of the larger family of ectoenzymes,
consisting in a set of molecules involved in the catabolism
and scavenging of extracellular nucleotides. This process
results in the synthesis of compounds that play critical
roles in cell homeostasis and metabolism, suggesting that
the physiological role of this complex family goes beyond
that of nucleotide recycling (298). Initially, it was thought that
one of the characteristics shared by several, though
not all, of the nucleotide-metabolizing ectoenzymes
was their ability to function in environments containing
only trace amounts of the substrate and where the final
product would be used prevalently inside the cell. This
initial view of enzymes working in an antieconomical
environment was later refined, thanks in part to more
sophisticated experimental approaches confirming that
substrates and final products are not so topologically
confined.
The Torino Lab decided to approach the challenges
derived from the intensely growing interest in this area by
1) prioritizing the human side, 2) deriving clues from the
ontogeny and phylogeny of CD38, and 3) trying to infer
information from disease models, which are some of nature’s best experiments. As an alternative to using CD38
knockout (KO) mice, we searched for naturally occurring
CD38⫺ individuals by analyzing more than 5,000 blood
samples from newborns. To do so, we tried to replicate
work previously done by our Institute with individuals
lacking the complement factors C2 and C4 (polymorphic
genes located inside the HLA region), whose absence is
occasionally detected in laboratory analysis. As the lack
of these gene products has no apparent influence on
normal life, the inference is that they are somehow redundant. Failing to identify any CD38⫺ individuals, we concluded that the absence of CD38 is incompatible with
human life. This was one of the first inconsistencies noted
between the human and the mouse model, where, although the CD38 KO is characterized by selected deficiencies in innate and adaptive immune responses, the animal
is nonetheless able to live and reproduce.
Research in Japan has played an impgfortant role. H.
Okamoto (Miyagi, Japan) focused on diabetes, designing
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
FIG.
scientific exchange between the different groups had objectively become extremely difficult. Admittedly, these
problems in communication persist: researchers working
in immunology risk finding it arduous to fully comprehend the biochemical theory and possibly vice versa. It
may be, however, that these problems are related more to
the unique nature of the molecule itself than to the inability of different specialists to understand one another.
Unraveling the secrets of a molecule that has survived
relatively unchanged over a 700 million year journey in
phylogeny is bound to take more than a decade; it would
seem naive to expect otherwise.
Thanks to continuing research efforts in the field,
new information is constantly becoming available. Crystallization of the molecule by Q. Hao (Ithaca, NY) marked
the long sought-after end of one quest on the one hand,
while opening up entirely new frontiers for exploration on
the other (216). Especially astonishing was a recent report by H. Higashida (Kanazawa, Japan), whose group
showed a link between CD38 and short-term social memory in mice, offering novel vistas on human autism (172).
Far from having coming to the end of our research, we are
poised on the threshold of challenging new studies and
experiences (Fig. 1).
The aim of this work is to provide an overview of
what has been accomplished in the field to date, while
keeping interpretation to a minimum. The Torino perspective is outlined in section X, but our own experience and
background have inevitably colored the entire work. This
will be obvious to any reader; however, it may also represent a strength of the presentation, and not necessarily
a drawback.
1. Key dates and findings in defining the CD38 family.
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an original model of insulin secretion, while the H. Hirano
group (Osaka, Japan) discovered that an old member of
the Boston harvest (originally termed Mo-5) was identical
to their anti-BST-1, providing the basis for the then-new
CD157. Thus CD38 became the prototype member of a
new family, whose molecular details were later analyzed
by Enza Ferrero, who also derived CD157 and CD38 by
gene duplication (91).
In the 1990s, this Lab became active in an international project overseen by the CD Workshop to use unknown antibodies for defining unknown molecules. While
comparing locally and externally produced anti-CD38 antibodies, Ada Funaro observed that one of our reagents
was able to induce cells to activate and proliferate (107).
This meant that the monoclonal antibody was endowed
with agonistic features, and raised the possibility that the
antibody was standing in for a soluble or cell-bound natural ligand. The key to identifying this unknown molecule
was found when U. Dianzani noticed selectin-type adhesion between CD38⫹ cells and endothelium (77). This
meant that we could raise a huge number of monoclonal
antibodies specific for the surface of endothelial cells and
test each of them for its ability to block adhesion between
cells expressing surface CD38 and the endothelium (63).
The problem was ultimately solved as the result of the
efforts of a young student, Silvia Deaglio. The finding of a
key monoclonal antibody (christened Moon-1 for propitiatory reasons) initiated a year of intense characterization of the nonsubstrate ligand for CD38, which was later
identified as CD31 (69).
One unintended consequence of increased interest in
CD38 was that, by the 1990s, researchers were constructing such increasingly complex models and theories that
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man immunodeficiency virus (HIV) infection, and chronic
lymphocytic leukemia (CLL) reflects again the historical
perspective and the availability of data from independent
groups. Admittedly, it is an arbitrary selection, but it was
made because they represent models where CD38 is used
for its ability to produce cyclic ADP ribose (cADPR) (i.e.,
diabetes), for a virus as a private surface receptor (i.e., HIV
infection), and for tumor cells as a noninnocent bystander,
leading to the acquisition of increased survival potential and
hence to a poor clinical prognosis (i.e., CLL).
Section IX reviews the limited number of studies and
unpublished experience on attempts to use CD38 in clinical applications. This includes conventional studies
where CD38 is used as a constitutive or inducible target,
to which antibodies are addressed as vectors for cytotoxic drugs or for purging protocols. An even more innovative approach is the use of CD38 to target tumors to be
bound by modified oncolytic viruses.
Section X includes the concluding remarks, intended
as a playground where to propose and discuss explanations for the several aspects that still need to be framed in
a scientific and plausible model. A space is dedicated to
proposing the vision of this Laboratory that the CD38
gene family represents a bridge between the innate and
adaptive immune systems. This is a way to provoke real
scientific approaches, discussions, and contributions to
answer the still open questions, to attract attention from
a wider audience of scientists, and to convince the medical community that CD38 is not (only) a cell activation
marker.
II. ONTOGENY AND TISSUE DISTRIBUTION
The expression of CD38 was first observed on thymocytes and T lymphocytes (23). As with many other
leukocyte surface molecules, this early finding biased the
direction of later research, which focused primarily on
CD38 present in lymphoid tissues. Further studies led to a
revised notion of the molecule’s distribution, and CD38
expression is now considered virtually ubiquitous, at least
in the immune system. However, the underlying mechanism of action of the molecule’s expression in different
cell lineages is still not entirely clear, and this is reflected
in the sometimes contrasting reports in the literature.
While measuring the surface expression of CD38,
several caveats apply. First, the expression of CD38 modifies significantly with age. The expression of CD38 measured in cord blood is extremely high in T cells (in 80 –
100% of both CD4⫹ and CD8⫹ T cell subsets) (24). The
majority of these cells remain positive up until 2 years of
age and decrease thereafter (237). Cord blood B cells also
express CD38 at high levels, at variance with the very low
numbers of CD38⫹ B cells seen in adults. Second, the
range of CD38⫹ T cells varies greatly in healthy individu-
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In setting out this review, we have attempted to
combine and reconcile the results of studies rooted in
different scientific backgrounds. We try to answer questions about where the molecules are expressed, what kind
of structure they have, what they do in vivo, whether they
are involved in disease, and whether they may find clinical
applications. It is our desire to make the subject matter
interesting and accessible to the widest possible audience, without sacrificing scientific detail or accuracy.
Section II focuses on tissue distribution and highlights changes induced by age and drug treatment. The
section is split into subsections that report on the expression of the molecules in the cells and tissues where
originally identified; the greater emphasis on CD38 than
on CD157 is a result of the larger body of data of the
former. Two tables provide easy reference to the data.
Section III focuses on analysis of the structure of
CD38 and CD157; once again, the evidence concerning
CD38 is more abundant than that on CD157. The section
includes early data coming from immunoprecipitation of
surface-labeled cells and more recent results coming from
crystallography.
Section IV presents evidence of the molecule’s functional role as a receptor. Different subsections offer details
concerning the existence of a ligand in humans and the
ability to transduce signals in human and murine models.
This area is the most controversial in terms of differences
between humans and rodents. A separate subsection is dedicated to CD157, the Cinderella of the family.
Section V offers a brief summary of the vast literature
on these molecules as enzymes and on the relevance of
their products in physiology and pathology. This is a
crucial component of the review 1) because of the very
peculiarity of the enzymatic functions themselves, and 2)
because it points to a clear link between the molecular
structures, pleiotropic functions, and products of key relevance for the life of a cell. A table is dedicated to the
regulation of the enzymatic activities by endogenous and
exogenous agents, an extremely important consideration
from the perspective of clinical transferability. A separate
subsection deals with the functional models described to
date.
Section VI reviews the results obtained using murine
models with inactivated CD38 and CD157 genes. The data
obtained have led to distinct progress in defining the roles
played by CD38 and, to a lesser extent, by CD157.
Section VII analyzes the phylogeny and gene organization of CD38 and CD157. Both the canonical and noncanonical aspects of the genes are presented, including
the presence of a genetic polymorphism for CD38. Phylogeny is viewed as a means of tracing the history of the
molecules and as a source of clues as to their functions
during the distinct steps of evolution.
Section VIII summarizes the evidence on the role(s)
played by CD38 in diseases. The choice of diabetes, hu-
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
als. Pregnancy is also characterized by a peculiar expression of the molecule, with a significant increase in the
percentage of CD38⫹CD8⫹HLA-class II⫹ lymphocytes.
This population peaks during the third trimester and decreases to normal levels 1 mo after delivery (242).
What follows is a summary of currently available data
on the distribution of CD38, arbitrarily split between immune and nonimmune cells.
A. Thymocytes and T Lymphocytes
B. B Lymphocytes
B lymphocytes were originally thought to be CD38⫺.
However, this assumption has been revised, mainly in
light of the fact that lymphomas, leukemias, and myelomas all express the molecule, and B cells are currently the
focus of many detailed studies. CD38 expression is tightly
regulated during B cell ontogenesis and is present at high
levels in bone marrow (BM) precursors; it is downregulated in resting normal B cells and is then reexpressed in
terminally differentiated plasma cells. This seesaw behavior suggests that CD38, though not a lineage marker, is
expressed at certain points during B cell development,
when cell-to-cell interactions are crucial (104, 227). CD38
has also proven extremely useful in classifying subsets of
functional mature B lymphocytes. Simultaneous evaluation of CD38 and IgD surface expression levels allowed
the identification of five discrete cell subsets corresponding to critical developmental stages of mature B lymphocytes (274). According to this model, CD38 expression is
induced upon naive B lymphocyte activation, peaks when
B cells enter the germinal center, decreases during centrocyte/centroblast differentiation, and completely disappears in memory B cells. Thus CD38 expression is one of
the early markers of mature naive B cell activation and is
Physiol Rev • VOL
upregulated before B cells undergo somatic mutations in
the IgV genes within the germinal center (51, 328).
C. Myeloid Lineage
CD38 expression has been reported in circulating
monocytes (256, 359) but not in resident macrophages. It
is also a novel marker of the transition of monocytes to
dendritic cells which is induced by inflammatory processes. The first step towards immature DC (iDC) is accompanied by progressive loss of surface CD38 as well as
of CD14, and by the simultaneous acquisition of CD1a
(88). Lipopolysaccharide (LPS) induces DC to shift to a
mature state. LPS-induced maturation of iDC is paralleled
by rapid reexpression of CD38 by the majority of the cells,
a process highly reminiscent of lymphocyte differentiation. CD40 ligation (a late T-cell-derived signal of DC
maturation operating in the secondary lymphoid organs)
induces a similar, although weaker, upregulation of CD38
to that of CD83. CD38 may be considered an early maturation marker induced by microbial molecules and cytokines produced during the early steps of innate immune
response. Late events (i.e., those driven by CD40 ligation)
are less important to the induction of CD38 (98).
As members of the myeloid lineage, circulating osteoclast and osteoblast precursors express CD38 on the
surface (310). Expression is maintained during tissue differentiation of these two populations (2).
CD38 is also expressed by cells of the innate immune
system, including circulating and residential natural killer
(NK) cells (229) and granulocytes (99, 100).
CD38 is also abundantly expressed in the BM, where
it apparently stains CD34⫺ committed and proliferating
precursors (34). However, the degree of stemness of
CD38⫹ cells is still being investigated. This is the main
reason caution must be exercised in the therapeutic use
of anti-CD38 antibodies (27).
D. Nonimmune Tissues
Functionally active forms of human CD38 were also
identified in the outer membrane of red blood cells (361)
and on platelets (290). It later became clear that CD38 is
widely expressed outside the immune system, often as a
cytoplasmic and nuclear molecule (90). Among solid tissues, the molecule is expressed by normal prostatic epithelial cells (200) and pancreatic islet cells (194, 231).
CD38 expression was also detected in perikarya and dendrites of many neurons, such as the cerebellar Purkinje
cells (244), in rat astrocytes (341), and in perivascular
autonomic nerve terminals (315) Other CD38⫹ cells include smooth and striated muscle cells (90), renal tubules
(45), retinal gangliar cells (184), and cornea (314).
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CD38 is expressed by a significant fraction of human
thymocytes, mainly at the double-positive stage. It is not
found on subcapsular double-negative thymocytes and is
only present on some medullary single-positive thymocytes (330). Within the circulating pool, CD4⫹/CD45RA⫹
naive T cells express CD38 (77), as does a subset of
regulatory CD4⫹/CD25⫹ T cells, at least in the mouse
system (291). CD38 is not expressed or is present at very
low levels in memory T cells (67). Among CD8⫹ T cells,
CD38 is strongly expressed during chronic infection; the
significance of CD38 expression in this subset is still
controversial and will be discussed in the section on
diseases. CD38 is also readily expressed at high levels by
the majority of peripheral blood mononuclear cells upon
in vitro and in vivo activation (226). Expression of CD38
on T cells residing in the tissues mainly depends on the
degree of their activation (67).
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1.
Distribution of CD38
Cell Population
Lymphoid tissues
Blood
Cord blood
Bone marrow
Eye
Prostate
Gut
Pancreas
Muscle
Bone
Kidney
T cells (precursors, activated)
B cells (precursors, activated)
Myeloid cells (monocytes,
macrophages, dendritic cells)
NK cells
Erythrocytes
Platelets
T and B
lymphocytes,monocytes
Precursors
Plasma cells
Cortical thymocytes
Germinal center B cells
Purkinje cells, neurofibrillary
tangles
Cerebral cortex (rat)
Cultured astrocytes
Cerebellum
Cornea
Retinal gangliar cells
Epithelial cells
Intraepithelial lymphocytes
Lamina propria lymphocytes
Small intestinal lymphatic
vessels (rat)
␤-cells
Sarcolemma smooth and
striated muscle
Myometrial smooth muscle
cells (rat)
Osteoclasts
Glomeruli
292
225, 262, 317
256
102, 225
361
290
115, 220, 287
262
7, 90
330
7
244
351
341
59
314
184
200
90
67
87
TABLE
174, 194
90
2.
Distribution of CD157
Cell Population
Reference Nos.
43, 80
Lymphoid tissues
Blood
322
45
Table 1 summarizes most of the reports available to
date on the distribution of CD38. Table 1 is divided into
lymphoid and nonlymphoid tissues.
Bone marrow
Thymus
E. CD157
Lymph nodes
After the first reports on CD38, it took over a decade
for scientists to identify the second member of the family.
Ironically, a specific monoclonal antibody for the molecule had been raised in the mid 1980s by the Harvard
group, the same which first described T10/CD38 (336).
Known as Mo-5, it was left in a sort of limbo until the
Hirano group, using an entirely different approach, independently raised a specific reagent for the molecule,
which they dubbed bone marrow stromal cell antigen-1
(BST-1) (175). Thanks to characterization of the target
and molecular sequencing, researchers collaborating at
the VI Workshop on Differentiation Antigens recognized
the molecular homology between Mo-5 and BST-1, its
sequence similarity with CD38, and also their analogy of
function (167). This research effort culminated in attribution of an independent cluster. Because CD157 is a newPhysiol Rev • VOL
Spleen
Nonlymphoid tissues
Liver
Vessels
Lung
Uterus
Skin
Gut
Peritoneum
Kidney
Pancreas
Other
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Neutrophils
Eosinophils
Basophils
Monocytes
Macrophages
Plasmocytoid dendritic
cells
B cell precursors
Myeloid precursors
Stromal cells
Nurse-like cells
CD3⫺/CD4⫺/CD8⫺
thymocytes (mouse)
Follicular dendritic
cells
Reticular cells (white
pulp)
Fetal B cell progenitors
Endothelial cells
Mast cells
Mast cells
Mast cells
Brush border, epithelial
cells of villi
Peyer’s patches
Stromal cells in
cryptopatches
Isolated lymphoid
follicles
Mesothelial cells
Macrophages/peritoneal
exudates
Collecting tubules
␣- and ␤-cells
Gingival fibroblasts
239
336, 346
336
140, 265, 336
162, 265
140
165, 239
239, 336
145, 175, 282
312
165, 166, 308, 342
A. Sapino, personal
communication
238
165
268
116, 346
346
116
238
238
329
329
295
239
238
176
260
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Thymus
Lymph nodes
Nonlymphoid tissues
Brain
Reference Nos.
comer of the family, data on its distribution are still scant
(Table 2).
Cytofluorographic analyses indicated that human
CD157 is expressed by synovial cells, vascular endothelial
cells, and follicular dendritic cells (140). Moreover, CD157
is also present on dermal fibroblasts; human mast cells
from lung, uterus, and foreskin; and mesothelial cells
from peritoneum (116, 295, 312, 346).
The earliest description of the distribution of murine
CD157 was obtained using the BP-3 monoclonal antibody
(239). The BP-3 antigen was originally described on early
progenitors of murine B and T lymphocytes and on fetal
liver B progenitors. The expression of CD157 during ontogenesis spans pre-B cells and circulating B cells with an
immature phenotype (IgMhigh/IgDlow) typical of cells recently migrated from BM (165). Analysis of CD157 expression in the thymus indicates its presence on pre-T cells in
fetal thymus (122, 123).
In the murine myeloid lineage, CD157 is expressed at
low levels by relatively mature myeloid cells in the BM
and at high levels by polymorphonuclear cells and stromal cells from the BM (239). Immunohistochemical stain-
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
ing of murine CD157 highlighted its expression within the
collecting tubules of kidney, on the brush border of intestinal epithelial cells, and on a subset of reticular cells in
lymph nodes, Peyer’s patches, and splenic white pulp
(238). Finally, CD157 was identified in mouse pancreatic
islet cells, including ␣ and ␤ cells (176).
III. CD38/CD157 STRUCTURE
A. CD38
Physiol Rev • VOL
facing each other and creating a cavity at the dimer
interface. The study also showed that a disulfide bond,
unique to CD38 and correlated with bifunctional activity,
occurs at the hinge region, implying that a conformational
change is necessary for enzymatic activities.
In a different approach, researchers tried to reconcile
signals, enzymatic functions, and cell-bound ligands, making use of clues inferred from murine models (355). We
performed a structural and functional analysis of CD38 in
XLA and other immunodeficiencies, using Epstein-Barr
virus (EBV)-immortalized B cells derived from such patients (228). Membrane CD38 was not significantly different from healthy controls in structure, epitope density,
enzymatic activities, or internalization upon binding of
agonistic monoclonal antibodies. However, the XLA-derived lymphoblastoid lines released relatively high amounts of
soluble CD38: immunoprecipitation from culture media of
XLA cells yielded a protein of ⬃78 kDa (p78), reacting in
western blot and displaying enzymatic activities and a
peptide map similar to that of membrane CD38. Other
posttranslational modifications were reported by the K.
Mehta group (Houston, TX), highlighting the presence of
a 190-kDa form (340). The tendency of CD38 to form
dimeric or multimeric complexes is not a specificity of
humans, being confirmed in murine B lymphocytes (249).
Establishing the location of the enzymatically active
site has been a long-term aim of investigation, and a
number of different strategies have been tried. The T.
Katada group (Tokyo, Japan) mapped the catalytic domains by expressing COOH-terminal deletion mutants of
CD38 in COS-7 cells (149). Mutants with fewer than 15
amino acids deleted at the COOH terminus of the 300amino acid wild-type molecule maintained nicotinamide
adenine dinucleotide (NAD) glycohydrolase (NADase) activity, whereas those with more than 27 amino acids
deleted did not. The general inference was that the
COOH-terminal 273–285 sequence bears the site of enzymatic activity. Introduction of site-directed mutation of
Cys-275, a conserved cysteine residue located in the 273–
285 sequence, completely abolished NADase activity. A
panel of selected anti-CD38 monoclonal antibodies was
tested using these mutants and various CD38 fragments as
targets in immunoblot analyses to define an epitope of the
agonistic anti-CD38 monoclonal antibodies. The epitopes
recognized by monoclonal antibodies inducing protein
tyrosine phosphorylation were mapped on an identical
site containing the COOH-terminal sequence of 273–285.
It was thus concluded that the discrete COOH-terminal
sequence not only plays a key role in the ecto-NADase
activity, but also constitutes the epitopes exploited by the
agonistic anti-CD38 monoclonal antibodies for transmembrane signaling (149).
The same issue was taken up by the P. Deterre group
(Paris, France), which showed that the epitopes recognized by distinct monoclonal antibodies and enzymatic
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CD38 was initially reported as a single chain of 45
kDa which was occasionally associated with a 12-kDa
molecule, making it reminiscent of a family of HLA class
I-like molecules known at that time as T6 (now CD1a)
(331). With the use of different technical approaches and
multiple sources of antigens, it was later shown that
purified CD38 is not associated with ␤2-microglobulin
(␤2m) (7). Two-dimensional isoelectrofocusing gel electrophoresis revealed 5 spots [isoelectric point (pI) range:
6.5 to 6.9]. Endoglycosidase-H treatment reduced the
mass of CD38 by ⬃20%, revealing a broader band centered at 36 kDa. Treatment of the CD38 molecule with
Staphylococcus aureus V8 protease yielded a single dominant band of 38 kDa, which contained the A10/IB4
epitope, the agonistic monoclonal antibodies (225). The
CD38 molecule was trypsin-resistant in denatured and
native conditions. It appeared as a glycoprotein comprising two to four N-linked oligosaccharide chains containing sialic acid residues. However, the various CD38⫹ cells
or cell lines did not reveal apparent biochemical differences (7).
Direct cloning (169) ruled out the possibility of homology with murine Qa2. Furthermore, the use of somatic
cell genetics indicated that the CD38 gene is located on
chromosome 4 (4p15), and thus outside the canonical
HLA locus in chromosome 6 (181).
The finding that CD38 is an ectoenzyme influenced
later studies, which were mostly based on investigation of
a link between structure and localization of the catalytic
site. Initially, the A. De Flora group (Genoa, Italy) demonstrated that none of the cysteine residues is essential to
the enzymatic role in CD38 and Aplysia proteins and that
disulfide bridges are essential for maintaining the monomeric and catalytically active structure of the molecule
(362). Later analysis of the crystal structure of ADP ribosyl cyclase (ADPRC) from Aplysia provided conclusions
also applicable to human CD38 (284). The Aplysia crystals are characterized by two domains separated by a
large cleft and connected by a hinge region. A distinct
pocket constituted by conserved residues is associated
with each domain.
The Aplysia cyclase homodimer provided a model
for CD38 and CD157, with the clefts of the monomers
847
848
MALAVASI ET AL.
plays an important role in driving cADPR to the catalytic
site through strong hydrogen bonding interactions (215).
The structure of CD38 proved difficult to establish,
but was finally determined by examining a product obtained from a construct with a missing transmembrane
segment and mutated glycosylation sites. The resulting
extramembrane domain is fully active in terms of enzymatic functions and is crystallized as head-to-tail dimers
(216). The crystal structure of the extramembrane domain, solved to 1.9 Å (59), showed that ␤-structures are
found mainly in the C-domain, while the helixes are in the
N-domain. These secondary structures of CD38 and Aplysia cyclase are thus very similar. The impossibility of cocrystallizing CD38 with substrates (which would be transformed
during crystallization) was overcome by using inactive
mutants in the construct (Fig. 2).
The overall structure of the CD38 molecule is “L”shaped and can be divided into two separate domains.
The NH2-terminal domain (residues 45–118 and 144 –200)
is formed by a bundle of ␣-helices (␣1, ␣2, ␣3, ␣5, ␣6) and
two short ␤-strands (␤1, ␤3); and the COOH-terminal
domain (residues 119 –143 and 201–300) consists of a
four-stranded parallel ␤-sheet (␤2, ␤4, ␤5, and ␤6) surrounded by two long (␣8 and ␣9) and two short ␣-helices
(␣4 and ␣7). These two distinct domains are connected by
a hinge region composed of three peptide chains, including residues 118 –119, 143–144, and 200 –201. A disulfide
bond (Cys-119 –Cys-201), which is unique in CD38, in
addition to the other five pairs of disulfide bonds (Cys64 –
Cys82, Cys99 –Cys180, Cys160 –Cys173, Cys254 –Cys275,
and Cys287–Cys296) conserved in ADPRC family members, further stabilizes the relative conformations of the
two domains by linking peptides 118 –119 with 200 –201.
The formation of the disulfide bond by residues Cys-119
and Cys-201 confirms the previous prediction (216, 284).
The membrane proximal domain is involved in binding the HIV coat protein gp120, resulting in a modulation
of viral entry into the target cell (303). This region is also
FIG. 2. Two views of a ribbon representation of soluble
human CD38 structure related by 90° rotation around a vertical
axis. (Figure kindly provided by Dr. Q. Hao, Cornell University,
Ithaca, NY.)
Physiol Rev • VOL
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sites are both sensitive to proteases and reducing agents.
Binding of the active site by specific monoclonal antibodies triggers conformational changes that shield critical
backbone bonds and disulfide bridges, including protection from proteolytic cleavage or reduction. This transconformation takes place irreversibly after incubation
with substrates (e.g., NAD) in the presence of dithiothreitol. The epitope is preserved, while enzymatic activity is
lost. The resulting paracatalytic inactivation is likely secondary to a covalent trapping of the intermediate of the
enzymatic reaction in the active site (21).
The group of H. C. Lee (Minneapolis, MN) used sitedirected mutagenesis to identify the enzymatic active site
of CD38. Replacement of Glu-226 (which corresponded to
the catalytic residue of the cyclase) by Asp, Asn, Gln, Leu,
or Gly results in complete loss of all enzymatic activities
of CD38, meaning that Glu-226 is most likely a crucial
catalytic residue. Homology modeling revealed that all of
these critical residues are clustered in a pocket near the
center of the CD38 molecule. The results also indicated a
strong structural homology between the active sites of
CD38 and the Aplysia cyclase (253). Later, the same
group used a similar technique to study the role of the
CD38 active site in ruling NAD cyclizing and hydrolyzing
activities. CD38 mutants were produced in yeast, purified,
and characterized by immunoblot. The results were consistent with Glu-146 being crucial in the specific and
selective control of the cyclase and hydrolase activities of
CD38 (127).
More recently, the crystal structure of the human
CD38 enzymatic domain complexed with cADPR and with
its analog cyclic GDP-ribose and NGD at different resolutions indicated that the binding of cADPR (or cGDPR)
to the active site induces significant structural rearrangements in the dipeptide Glu146-Asp147 (217). This provides direct evidence of a conformational change at the
active site during catalysis. Furthermore, the same paper
confirmed that Glu-226 is critical for catalysis, but also
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
thought to be the one interacting with CD31 (U. Dianzani,
personal communication).
In addition to the existence of a membrane form, a
soluble form of CD38 (sCD38) was identified in cell culture supernatant of activated T lymphocytes, in several
tumor cell lines, and in vivo in normal (fetal serum and
amniotic fluid) and pathological [serum and ascites from
patients with multiple myeloma, and serum from patients
with acquired immune deficiency syndrome (AIDS)] biological fluids (103, 208).
B. CD157
Physiol Rev • VOL
140, and Glu-178, are similar in configuration, including
the side chains. These two Trp residues and the Glu
residue play key roles in substrate recognition and the
catalytic reactions. In each catalytic cleft of the dimeric
enzyme, substrates are recognized predominantly through
van der Waals interactions with two Trp residues, leading
to appropriate exposure of the N-glycosidic bond of NAD
near a catalytic Glu residue. This conformation of the
catalytic cleft also implies cyclization between the adenine base and ribose. The three key residues are invariant
among the sequences of CD157, CD38, and Aplysia cyclase, which share a common substrate recognition mode
and catalytic scheme (352).
CD157 and Aplysia cyclase show a better match with
each other than with CD38 (216), confirming at the structural level the results of evolutionary studies.
IV. RECEPTORIAL FUNCTIONS
A. Historical Perspective
The finding that CD38 is a receptor was largely serendipitous. While performing a series of tests as part of
the CD Workshop, an international collaborative study of
cell surface molecules of human leukocytes, our laboratory noticed that binding of the A10/IB4 monoclonal antibody was followed by proliferation effects on preparations of human peripheral blood mononuclear cells
(PBMC). This phenomenon proved to be accessory cell
dependent and interleukin (IL)-2 dependent and additive
with both the CD2 and CD3 activation pathways (107).
Further experiments showed that the CD38 molecule is
also involved in the transduction of activation and proliferation signals, which are line unrestricted (226). Analogous results were observed in a murine model by another
group following a similar approach: the NIM-R5 monoclonal antibody was found to increase intracellular Ca2⫹ and
to induce the expression of HLA class II molecules on
resting B lymphocytes. Moreover, monoclonal antibody
treatment proved weakly mitogenic on its own, but was
strongly comitogenic when used with IL-4 (302).
The most plausible explanation for these results was
that CD38 is a cell surface molecule with receptorial
functions, most likely working in synergy with other receptors. This notion was substantiated by the identification of a specific ligand for CD38, expressed mainly by
endothelial cells (63). Fifteen years have passed since
those first attempts to shed light on the role of CD38, and,
in the meantime, scores of papers have been published on
the signaling properties of the molecule. The emerging
picture is multi-faceted and complex. For the sake of
clarity, this text has been organized as follows: 1) human
and murine CD38 are treated in separate sections because
of their marked differences in terms of tissue distribution
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Human CD157 is a single chain of 42–45 kDa anchored to
the membrane via a glycosylphosphatidylinositol (GPI) anchor (167). Deglycosylated CD157 is 31 kDa (142).
CD157 exhibits both monomeric and dimeric forms
when heterogeneously expressed in MCA102 and CHO
fibroblasts. The dimers can dissociate into monomers
when SDS-PAGE is performed in the presence of ␤-mercaptoethanol, suggesting intermolecular disulfide bond(s)
in the dimers. It seems plausible that the dimerization is a
result of the high-density surface expression of CD157 on
the recombinant cells.
When expressed and released into culture medium as
a soluble form without the COOH-terminal GPI anchor,
CD157 was found to further aggregate into oligomers,
which could only be dissociated under reducing conditions (213).
The crystal structures of the extracellular region of
human CD157 at atomic resolution was determined in the
free form and also in complexes with five substrate analogs, namely, nicotinamide, nicotinamide mononucleotide,
ATP, ethenoNADphosphate (NADP⫹), and ethenoNAD. The
CD157 subunit is divided into two domains, termed the N
domain (residues 2– 68, 98 –150) and the C domain (residues 69 –97, 151–251), which are connected by a hinge
region of three peptide chains. All 10 cysteine residues,
conserved among the cyclase family, form disulfide
bonds, as observed in the structure of Aplysia cyclase
(352). The internal architecture of each domain is essentially identical to that of the Aplysia cyclase. Each subunit of the CD157 dimer contains a substrate binding cleft,
formed by the N and C domains. This large cleft, surrounded by ␣4, ␣5, ␣6, and ␣7 helices as well as ␤1 sheet,
is covered mainly by hydrophobic and acidic residues,
and its overall dimensions are essentially the same as
those of the Aplysia cyclase.
Mutational analyses of CD38 and Aplysia cyclase
suggested that the cyclase activity of CD157 requires Trp77, His-81, Ser-98, Asp-99, Asp-107, Trp-140, and Glu-178
(253, 254). Because of their position in the cleft, these
residues are well superimposed between CD157 and
Aplysia cyclase. The three invariant residues, Trp-77, Trp-
849
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MALAVASI ET AL.
and modalities of signal transduction; and 2) each section
has been subdivided by cell lineage, to make the vast
amount of data now available on the signaling properties
of CD38 easier to navigate.
Other ligands proposed for CD38 include hyaluronate
(261) in humans and an as yet unidentified 130-kDa glycoprotein in mouse (348).
C. Signaling in Human Models
B. Evidence of a Cell-Bound Ligand
1. PBMC and T lymphocytes
Physiol Rev • VOL
CD38 ligation by monoclonal antibodies was shown
to increase [3H]thymidine incorporation (107). Subsequent studies explored the nature and (in)dependence of
the signals mediated by CD38 by comparing them with
what was known at the time about TCR/CD3 and CD2. As
with these two molecules, ligation of CD38 induced multiple cytokine mRNA expression in cultured PBMC. What
was surprising was the significant overlap between the
types of mRNA molecules induced by CD38 and by TCR/
CD3 activation. However, CD38 and CD3 activation differed in two main respects. IL-2 mRNA levels remained
low upon CD38 ligation, while IL-1␤ and IL-6 mRNA
steadily accumulated (14). Analogous studies were then
performed on purified normal lymphocyte populations.
CD38 ligation in purified peripheral blood T cells was
followed by induction of discrete cytokines. Of these,
IL-6, granulocyte-macrophage colony-stimulating factor
(GM-CSF), interferon (IFN)-␥, and IL-10 mRNA expression were consistently found. Low levels of IL-2, IL-4, and
IL-5 mRNA were also detected in the majority of CD38activated T lymphocytes from all the individuals studied (13).
These anecdotal observations found support and explanation in experience gleaned at the bench. Researchers reported rapid and specific comodulation of the TCR/
CD3 complex following CD38 ligation. The model hypothesized at the time was that CD38 was an accessory
receptor, working in association with lineage-specific receptors. This prompted studies of lateral associations
between CD38 and TCR/CD3, BCR/CD19/CR2, and CD16
in T, B, and NK cells, revealing physical proximity and
functional interactions (102). It was generally assumed
that TCR/CD3, CR2, and CD16 were ligand-binding structures within their respective lineages, whereas CD38
was thought to be involved in the intracellular transduction of the signals. Although this model has been partly
revised, CD38 is still believed to be physically and functionally linked to supramolecular signaling complexes in
the T, B, NK, and myeloid lineages (Fig. 3).
The earliest evidence indicating a functional interrelationship between TCR/CD3 and CD38 emerged from
studies using Jurkat T cell mutants. The mutants lacked a
full complement of CD3 structures and the ability to
signal via CD38. Reconstitution of a functional TCR/CD3
complex was accompanied by recovery of CD38 signaling.
Moreover, like TCR/CD3, CD38 was able to induce apoptotic cell death of Jurkat cells, an event which was paralleled by specific upregulation of the Fas molecule and
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The first clues to the existence of a nonsubstrate
ligand for human CD38 emerged from experiments showing that anti-CD38 monoclonal antibodies blocked CD4⫹/
CD45RA⫹ T cell adhesion to endothelial cells. Inhibition
mediated by anti-CD38 monoclonal antibodies was apparent in binding assays that minimized integrin functions.
This suggested that CD38 mediates weak cell binding to
endothelium, effective even in dynamic conditions. Such
behavior was reminiscent of that of selectins, which are
adhesion molecules involved in leukocyte rolling on vascular endothelial cells and lymphocyte homing (77). We
thus surmised that the endothelial cell membrane also
harbors a ligand for CD38 and set out to test this hypothesis by producing a panel of murine monoclonal antibodies specific for human umbilical vein endothelial cells
(HUVEC). Only a few reagents proved to consistently
inhibit CD38-mediated adhesion of several cell lines to
HUVEC (63). One of them, Moon-1, was shown to recognize CD31/PECAM-1, as evinced by 1) cross-inhibition
assays between Moon-1 and reference anti-CD31 monoclonal antibodies; 2) sequential immunoprecipitation experiments with known anti-CD31 monoclonal antibodies,
and 3) reactivity of Moon-1 with CD31 transfectants. Furthermore, CD31 and CD38 cognate interactions were
found to modulate heterotypic adhesion as well as to
initiate cytoplasmic Ca2⫹ fluxes identical to those obtained by means of agonistic anti-CD38 monoclonal antibodies. The interplay between human CD38 and its ligand
CD31 is thus crucial to the regulation of cell life and is
fundamental in the migration of leukocytes (as well as of
CD38⫹ cancer cells) through the HUVEC wall (69). These
results were confirmed by using a recombinant soluble
form of the human CD38 molecule, which binds to soluble
recombinant murine CD31 (highly homologous to the human counterpart). The binding domain was found to reside in the first three NH2-terminal domains of the ectocellular portion of the CD31 molecule (146).
CD38/CD31 cross-talk has been extensively analyzed in a number of different environments ranging
from T lymphocytes to B, NK, and myeloid cells, from
normal to pathological situations (reviewed in Ref. 66).
The experimental system relied on the use of murine
fibroblasts transfected with the human CD31 gene. All
published accounts confirm that the effects observed
with the agonistic monoclonal antibody can be reliably
reproduced using the natural ligand. Results from specific papers are presented below.
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
851
which could be inhibited by cyclosporin A (251). A molecular explanation for these observations was found:
CD38 ligation led to complete tyrosine phosphorylation of
both CD3-␨ and CD3-⑀ polypeptide chains (365). As it
turns out, however, the CD3-␨ immunoreceptor tyrosinebased activation motifs are not necessarily required for
CD38 signaling in T cells. Indeed, cross-linking of CD38 or
CD3 in TCR⫹ T cells that express a CD3-␨ mutant lacking
the cytoplasmic domain still induces tyrosine phosphorylation of CD3-⑀, ZAP-70, LAT, and Shc (364). Detailed
analysis of the cytoplasmic events implemented immediately after binding of the agonistic monoclonal antibody
revealed tyrosine phosphorylation of phospholipase C
(PLC)-␥1, c-Cbl, ZAP-70, and Shc. CD38 signaling also
induced CD69 expression and promoted Ras-dependent
events, e.g., Erk2 mobility shift and increased kinase activity. CD38 ligation in JCam-1 (a Jurkat mutant lacking
Lck) failed to induce substrate tyrosine phosphorylation
or activation of Erk2 (366).
Our laboratory explored the interrelationship between CD38 and TCR/CD3 through comparative analysis
of the events implemented by CD38 ligation in circulating
versus residential T lymphocytes. The residential T cells
adopted, in this case those colonizing the intestinal lamina propria (LP), proved to be relatively refractory to
TCR/CD3-mediated signaling (281). Also, the results
showed that, unlike peripheral blood T lymphocytes, LP T
cells do not mobilize Ca2⫹ upon CD38 ligation and that
the impaired response is due to a failure to activate
PLC-␥. Another difference in the two cell populations was
Physiol Rev • VOL
the ratio of cytokines secreted upon CD38 engagement.
These findings suggested that CD38 is operative in an
environment where the TCR/CD3 complex is apparently
refractory to signals (67). From a teleological perspective,
it seems logical that CD38 recruits the receptor most
conducive to its signaling activities in each lineage and
environment.
More recently, lipid rafts have been attributed key
roles in the initiation of CD38-mediated signals. Indeed,
lipid rafts are constitutively highly enriched in CD38,
while cholesterol depletion substantially reduces CD38mediated signaling. CD38/raft association may thus improve the signaling capabilities of the molecule through
the formation of protein/lipid domains where signalingcompetent molecules are recruited (364). This issue was
investigated in detail in a follow-up paper by the same
group which showed that most CD38 is preassembled in a
subset of Brij98-resistant raft vesicles, containing high
levels of Lck and of the CD3-␨ subunit, the latter directly
associated with CD38. CD38 engagement induces LAT
and Lck to be tyrosine phosphorylated exclusively in
Brij98-resistant rafts (252). The relevance of Lck for CD38
signaling was confirmed in experiments showing a physical association between the cytoplasmic tail of CD38 and
the Src homology 2 domain of Lck. These findings strongly
suggested that CD38 ligation transduces activatory signals
for T cells by means of the associated Lck (46).
Although CD38 was initially studied in the thymus
(23), later attention shifted mainly to its presence in circulating leukocytes and leukemias. However, a recent
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FIG. 3. Schematic representation of the supramolecular complexes including CD38 in different cell lineages. CD38 is characterized by the
unique property of establishing strong lateral associations with professional signaling complexes, varying according to cell lineage, differentiation
steps, and microenvironment. The CD38-containing complexes are preferentially localized in rafts (represented in yellow in the picture) to start
signal transduction.
852
MALAVASI ET AL.
report addressed the signaling events mediated by CD38
in immature T cells. It showed that CD38 enhances apoptosis in thymocytes when it is cross-linked with a goat
anti-mouse antiserum. It has the same effect when crosslinked with the CD31 ligand expressed by thymic epithelial cells or transfected into murine fibroblasts. Thymocyte death was also enhanced when CD38 interacted with
CD31 expressed by accessory cells (330). These results
confirmed the observations obtained using the Jurkat
model (251).
2. B lymphocytes
Physiol Rev • VOL
3. Myeloid cells
Interest in the behavior of CD38 in myeloid cells
stemmed from findings that the molecule is readily and
consistently upregulated upon retinoic acid (RA) exposure in immature myeloid cells and acute promyelocytic
leukemia blasts (83). The T. Katada group (Tokyo, Japan)
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Analysis of CD38 functions in human B lymphocytes
originated from studies of the lymph nodes, where the
molecule is expressed at high density. The M. Ferrarini
group (Genoa, Italy) reported that CD38 ligation prevents
apoptosis of human tonsillar germinal center (GC) B cells.
This effect was specific for the IB4 monoclonal antibody
and was not observed with other reagents, even when
tested over a wide range of concentrations (367). The
results in B lymphocytes were thus consistent with those
in PBMC and T lymphocytes.
Attention was then turned to analyzing CD38 functions in the BM. By this time, the notion that CD38 was an
ectoenzyme was generally well established. In contrast to
results obtained using mature B lymphocytes, CD38 ligation in stroma-supported cultures of human B cell progenitors strongly inhibited B lymphopoiesis. This block in
differentiation was due both to inhibition of DNA synthesis and to induction of apoptosis. Enzymatic activities
were not influenced (positively or negatively) by monoclonal antibody ligation. Indeed, no changes in NAD⫹
hydrolysis or cADPR and ADPR production could be detected after CD38 ligation. Likewise, the addition of
NAD⫹, ADPR, or cADPR to cultures of lymphoid progenitors failed to offset the inhibitory effects mediated by
anti-CD38 monoclonal antibodies (204). This was the first
of many studies to indicate that the agonistic monoclonal
antibody binding has no influence on, nor is influenced by,
enzymatic activities. It was thus hypothesized that the
receptor and enzyme activities are two independent functions of the same molecule.
The same studies also revealed that CD19 is a major
component of the CD38 signaling cascade in B cell precursors, serving as a cell surface membrane docking site
for cytoplasmic kinases. Although they showed no physical link, CD38 and CD19 activated a similar set of kinases
in human immature B cells (189) (Fig. 3).
CD38 ligation by the agonistic monoclonal antibody
was followed by dimerization and tyrosine phosphorylation of the protein kinase syk and by increased syk kinase
activity. CD38 dimerization also induced tyrosine phosphorylation of PLC-␥ and of the p85 subunit of phosphatidylinositol 3-kinase (PI3K). These results are consistent
with those obtained using T cell models (313). Btk was
not tyrosine phosphorylated upon CD38 ligation, a peculiarity of human B cell precursors. However, btk is essential for CD38-mediated signals in murine B cell models
(see below). A subsequent work of the same group specifically addressed this point and identified tyrosine phosphorylation of Tec, but not of btk, in RS4;11 cells following CD38 ligation (191). PI3K activity was shown to be
essential to the process of CD38-mediated inhibition of
lymphopoiesis. Furthermore, cbl and PI3K were shown to
be regulatory molecules whose activation suppresses cell
proliferation and apoptosis in immature lymphoid cells
(190).
There is strong evidence that CD38 channels an activation/proliferation signal in human mature B cells.
Moreover, the CD38 pathway displays several features of
autonomy from the known surface receptors. CD38 ligation in circulating human B cells was shown to induce
expression of 1) CD25, 2) HLA class II, and 3) mRNA for
selected cytokines. The final outcome was proliferation.
Similar effects were observed on B blasts. In no instance
did cross-linking of CD38 induce immunoglobulin production (105).
CD38 signaling in B lymphocytes was recently taken
up again by our group, almost a decade after the seminal
work of D. Campana (Memphis, TN). Interest in CD38
signaling in human B cells was sparked by reports of the
molecule’s direct involvement in CLL both as a marker
and as a pathogenetic agent (see relevant section). We
have broached the issue once again, equipped this time
with evidence from the study of T and myeloid cells that
CD38 is a component of supramolecular complexes that
reside mostly within lipid rafts. The results of our analysis, performed on tonsil B lymphocytes and on B cell
lines, indicate that CD38-mediated signals are tightly regulated at three distinct levels. The first concerns the structural organization of CD38, which is clearly divided into
monomeric and dimeric forms. The second is based on
the dynamic localization of CD38 molecules in lipid microdomains within the plasma membrane. Lateral associations with other proteins, namely, with the CD19/CD81
complex, determine the third level of control. Raft localization and association with the CD19 complex are prerequisites for CD38-mediated signals in tonsillar B cells
and in continuous lines, as shown by loss of CD38-mediated signals upon lipid raft disruption and/or silencing of
CD19 (72).
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
Physiol Rev • VOL
tibody to the cultures induced a profound reduction of the
most mature CD34⫺/MPO⫹⫹ cell population, which includes pro-myelocytes, myelocytes, and meta-myelocytes.
The effects were strong enough to be maintained across
species: CD38 ligation of 32D cells (a murine myeloid cell
line transfected with human CD38) powerfully suppressed cell growth and survival (337).
Ligation of CD38 expressed by circulating monocytes
inhibited superantigen-induced T lymphocyte proliferation. This effect was likely due to the implementation of
an active signaling pathway, inducing tyrosine phosphorylation of several intracellular proteins (including c-cbl
and the fgr and hck kinases). This would indicate that
CD38 plays a role in the transduction of signal(s) involved
in superantigen-induced activation of monocytes, operating in synergy with HLA class II (359). The same group
recently built on these results by showing that CD38 and
HLA class II are physically and functionally associated
within lipid rafts of human monocytes. Furthermore, the
integrity of these domains is required for HLA class II and
CD38 signaling events. It was demonstrated that tetraspanin CD9 is a partner of the CD38/HLA class II complex and that HLA class II, CD38, and CD9 share a common pathway of tyrosine kinase activation in human
monocytes (360) (Fig. 3).
CD38 expression on human monocytes is finely
tuned in response to the proinflammatory cytokine IFN-␥.
IFN-␥ is a strong upmodulator of CD38, while lipopolysaccharide (LPS), tumor necrosis factor (TNF)-␣, and
granulocyte-macrophage colony stimulating factor (GM-CSF)
had no detectable effects. CD38 upregulation is paralleled
by increased ADPRC/cADPR hydrolase activities (256).
The final outcome of CD38 signaling in circulating monocytes includes secretion of IL-1␤, IL-6, and IL-10 cytokines
(206).
More recently, attention has been turned to dendritic
cells. CD38 was seen to be downmodulated during differentiation to immature monocyte-derived dendritic cells
(MDDC) and expressed again upon maturation. The extent of CD38 expression is dependent on the stimulus
adopted (LPS ⬎ IFN-␥ ⬎ CD40 cross-linking). De novosynthesized CD38 is enzymatically active, and its expression in mature (m) MDDC is dependent on NF-␬B activity.
However, CD38 is not merely a maturation marker but
also mediates signaling in mMDDC, where it maintains its
functions as a receptor. Activation via agonistic anti-CD38
monoclonal antibodies induces upregulation of CD83 and
secretion of IL-12, whereas disruption of CD38/CD31 interactions inhibits CD83 expression, IL-12 secretion, and
MDDC-induced allogeneic T cell proliferation (88).
The functional role of CD38 in MDDCs was analyzed
in a follow-up paper by the Clara M. Ausiello group
(Rome, Italy). They showed that CD38 signaling ensures
efficient chemotaxis and transendothelial migration
driven by CC chemokine ligand 21 (CCL21). Additionally,
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next investigated the intracellular signaling mediated by
CD38 in RA-differentiated myelomonocytic HL-60 cells.
The initial results revealed that c-cbl is one of the most
prominently tyrosine phosphorylated substrates (197).
These results suggest that c-cbl is a common substrate in
the CD38 signaling pathway, regardless of cell lineage or
differentiation stage. Later, it was shown that the p85
subunit of PI3K was immunoprecipitated with anti-cbl
antibody only when c-cbl was tyrosine phosphorylated.
PI3K activity was also observed in the immunoprecipitated fractions containing tyrosine-phosphorylated cbl
(235), confirming results using T and B cell models.
The final effect of CD38 ligation in myeloid cell lines
was to intensify the superoxide generation induced by
chemotactic formyl-Met-Leu-Phe (fMLP) receptors. CD38
signaling alone did not trigger superoxide generation,
suggesting that the CD38-induced tyrosine phosphorylation is involved in cross-talk with the chemotactic receptor/G1-mediated signal transduction pathway. This crosstalk results in the enhancement of superoxide generation,
probably through the activation of PI3K (339). Further
investigation by the same group revealed that the profile
of tyrosine phosphorylated proteins by HB-7 monoclonal
antibody was identical to that induced by cross-linking of
Fc␥ receptors II (Fc␥RII/CD32). Furthermore, Fc␥RII itself was tyrosine phosphorylated in the treated cells.
These results indicate that anti-CD38 monoclonal antibody-induced tyrosine phosphorylation and its associated
cell response might be mediated through the Fc␥RII-induced signaling pathway, possibly resulting from stimulation of the cell surface human Fc␥RII with the murine
IgG Fc domain (IgG1 subclass) of CD38-ligated monoclonal antibodies (161). The possibility that the effects observed with the IB4 agonistic monoclonal antibody were
mediated via FcR was ruled out by using F(ab⬘)2 preparations. The divalent monospecific antibody fragment
maintained all the effects mediated by the intact IgG2a
molecule, which is generally poorly bound by human
FcRs (107). However, the observation by Inoue et al. (161)
may also be read in a different light, highlighting interaction between CD38 and FcRs. Similar results have also
been reported in NK cells and are discussed in the relevant section.
In addition to superoxide generation, the CD38 signaling pathway may be linked to proliferation, as observed in different cell lines. CD38 ligation caused a dosedependent increase in the number of colony forming units
(CFU) and increased cell division in BM. Furthermore, the
anti-CD38 monoclonal antibody controlled proliferation
of AML colony-forming cells in five out of six AML patients tested (196).
Using the same approach adopted with B cell precursors, the Campana group used stroma-supported cultures
to assess the effects of CD38 ligation on myeloid differentiation. The addition of anti-CD38 T16 monoclonal an-
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CD38 signaling contributes to the longevity of LPS-matured MDDCs after growth factor withdrawal. A further
effect is the production of IFN-␥ by cocultured T lymphocytes, thus affecting Th1 polarization. From a molecular
stand point, CD38 was found to be laterally associated
with the CCL21-specific CC chemokine receptor 7 and
with CD83 and CD11b. It was also found to localize in
membrane lipid domains, as was also observed in monocytes and T and B lymphocytes (98) (Fig. 3).
4. Lymphokine activated killer and NK cells
Physiol Rev • VOL
5. Neutrophils
Investigation of the role and expression of CD38 in
neutrophils was prompted by studies on CD38 KO mice,
where CD38 was demonstrated to play a nonredundant
role in neutrophil chemotaxis (271). Information concerning human cells is limited and mostly focused on CD157.
However, the T. E. VanDyke group (Boston, MA) showed
that IL-8 or fMLP exposure readily removed CD38 from
the neutrophil surface, while mRNA levels remained stable. This effect is dependent on p38 mitogen-activated
protein (MAP) kinase signaling (100).
The role of CD38 in neutrophil chemotaxis relates to
the enzymatic activities leading up to cADPR production.
The Frances E. Lund group (Saranac Lake, NY) found that
a cADPR antagonist and a CD38 substrate analog inhibited chemotaxis of human phagocytic cells towards a
number of fMLP-like-specific ligands. Moreover, the
cADPR antagonist blocks chemotaxis of human monocytes to CXCR4, CCR1, and CCR5 ligands. According to
this model, cADPR is responsible for increasing intracellular free Ca2⫹ levels following chemokine binding.
Emerging evidence also attributes a crucial role to ADPR
(273).
D. Signaling in Murine Models
The signaling properties of murine CD38 have been
studied mostly in B cell models. This is a natural reflection of the mouse system environment, where B cells
score the highest levels of CD38, and T and NK cells show
only marginal expression. More recently, the focus has
shifted to neutrophils and dendritic cells, as a consequence of the phenotype of CD38 KO mice.
1. B lymphocytes
The initial observation was that the NIM-R5 monoclonal antibody, a rat anti-murine CD38, increased intracellular Ca2⫹ due to influx from the extracellular milieu
via Ca2⫹ channels. It also induced resting B lymphocytes
to increase expression of HLA class II molecules and
prepared the cells for “spreading” in the presence of
immobilized anti-HLA class II antibody. Furthermore,
NIM-R5 monoclonal antibody induced B cells activated
in vitro to proliferate and be rescued from apoptosis
(302).
Another independent study on the role of CD38 in
resting B lymphocytes found that CD38 ligation resulted
in multiple protein tyrosine kinase activities, thus attributing to CD38 a potentially central role in the transduction
of signals leading to B cell activation (187).
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The role of CD38 in lymphokine activated killer
(LAK) cells first came under scrutiny when it was observed that ligation with the monoclonal antibody was
followed by a dramatic surge in the release of cytokines
(GM-CSF, IFN-␥, TNF-␣, and TNF-␤). These effects were
observed in both TALL-104 and LAK cells (37).
Further study by the U. Kim group (Seoul, Korea) led
to the discovery of a functional loop involving IL-8 and
CD38. According to this model, CD38 is stimulated by sequential activation of the IL-8 receptor, inositol trisphosphate (IP3)-mediated Ca2⫹ rise, and cGMP/protein kinase G.
It also plays an essential role in IL-8-induced migration of
LAK cells (288). These observations have resulted in the
finding that the nonmuscle myosin heavy chain IIA protein (MHCIIA) associates with CD38 upon IL-8 stimulation
and that their association depends on PKG-mediated
phosphorylation of MHCIIA. Binding studies using purified proteins revealed that the association of MHCIIA with
CD38 occurred through the tyrosine kinase Lck. Moreover, all three molecules coimmunoprecipitated upon IL-8
stimulation of LAK cells. IL-8 treatment of LAK cells
resulted in internalization of CD38, which colocalized
with MHCIIA and Lck. These findings demonstrate that
the association of phospho-MHCIIA with Lck and CD38 is
a critical step in the internalization and activation of CD38
(289).
CD38 is also expressed by resting and activated NK
cells. Ligation of the molecule in circulating NK cells
proved to be followed by a significant rise in the intracellular concentration of Ca2⫹, by increased expression of
HLA class II and CD25, and by tyrosine phosphorylation
of discrete cytoplasmic substrates. The phosphorylation
cascade involved CD3-␨ and Fc␥RI chains, ZAP-70, and
c-Cbl. The long-term effects of CD38 signaling included
release of IFN-␥ and GM-CSF and induction of cytolytic
effector functions (229). As shown in other lineages, CD38
on NK cells forms part of a supramolecular complex that
comprises CD16. Indeed, a functional CD16 molecule is a
necessary and sufficient requisite for CD38 to control an
activation pathway that includes Ca2⫹ fluxes, tyrosine
phosphorylation of ZAP-70 and ERK, secretion of IFN-␥,
and cytotoxic responses. Fluorescence resonance energy
transfer and cocapping experiments indicated surface
proximity between CD38 and CD16 (73) (Fig. 3).
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
Physiol Rev • VOL
rather than on the actual turnover or generation of products.
The alleged independence of receptor and enzyme
activities was recently confirmed in a report by the same
group. The authors showed that anti-CD38-induced apoptosis of Ba/F3 cells, a murine pro-B line, is affected neither by blocking the Ca2⫹-mobilizing activity of cADPR
nor by inhibiting intracellular or extracellular Ca2⫹ mobilization. Furthermore, 1) apoptosis is also unaffected by
blocking CD38 enzyme activity with 2⬘-deoxy-2⬘-fluoronicotinamide arabinoside adenine dinucleotide and 2) Ba/F3
cells expressing catalytically inactive mutant forms of
CD38 still undergo apoptosis upon CD38 cross-linking.
Anti-CD38-induced apoptosis was found to be dependent
on tyrosine kinase and caspase activation. In addition,
this process appears to be intensified by the presence of
membrane microdomains. Thus the receptor-mediated
functions of CD38 can operate separately from its enzyme
activity, thus reinforcing the view that CD38 plays multiple, but independent, biologic roles (221).
The signaling pathway implemented upon CD38 ligation in murine B cells was first studied in mature, resting
B cells, where CD38 induced proliferation is in turn enhanced by cosignals such as IL-4 and LPS. Somewhat in
agreement with what has been described for human
monocytes, CD38-induced proliferation is abrogated by
Fc␥RII engagement. This inhibition can be brought about
by adding anti-Fc␥RII Ab during culture, suggesting that it
delivers a potent negative signal to CD38-activated B
cells. These findings indicate that Fc␥RII can act as a
regulatory molecule that modulates CD38 signals in vivo
(266).
The CD38 pathway was then tested in a cell line
lacking the cytoplasmic domain of CD38. Results indicated that CD38 ligation induced tyrosine phosphorylation with an intensity and kinetics similar to those seen
with the entire protein. It also induced cell aggregation
and decreased cell recovery. This suggests that CD38
triggers remarkably similar signaling pathways in human
and murine immature B cells and supports the existence
of accessory transmembrane molecules associated with
CD38 (192).
Looking further downstream, CD38 ligation of murine splenic B cells activated members of the NF-␬B/Rel
family of proteins, including c-Rel, p65, and p50. Activation of NF-␬B-like proteins by CD38 is not observed in
splenic B cells from btk⫺/⫺ mice, or in the presence of
inhibitors of protein kinase C (PKC) and PI3K, also suppressing NF-␬B activation in CD38-activated B cells. This
would seem to imply that activation of btk, PI3K, and PKC
plays, at least in part, important roles in the induction of
NF-␬B in CD38-stimulated murine B cells. It thus appears
that NF-␬B proteins play an essential role in the induction
of germline ␥1 transcripts by CD38-ligated murine B cells,
giving rise to the production of IL-5-induced IgG1 (177).
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However, B lymphocytes from unstimulated X-linked
immunodeficient (xid) mice proved unresponsive to CD38
ligation, both in terms of proliferation and surface antigen
modulation. This was the first clue that btk is either an
integral component or an indirect regulator of the CD38induced signal transduction pathway (301). CD38 ligation
was later found to induce tyrosine phosphorylation of btk,
at variance with what was reported for the human counterpart (313), and also to enhance expression of the IL-5receptor ␣-chain, suggesting a functional synergy between the CD38 and IL-5 signaling pathways (185).
Other studies showed that the proliferative response
and IL-5 receptor ␣-chain expression of B cells from
fyn-deficient (Fyn⫺/⫺) and lyn-deficient (Lyn⫺/⫺) mice
were impaired by anti-CD38 monoclonal antibody CS/2. B
cells from fyn/lyn double-deficient (Fyn/Lyn⫺/⫺) mice
showed no response to CS/2 monoclonal antibody. These
results indicate that the CD38 signaling pathway requires
the presence of both Fyn and Lyn, and that their signals
are synergistic (355).
In the search for partners for CD38 or for associated
molecules or signaling pathways, a striking relationship
was observed between CD38-mediated mitogenesis and
the ability of surface IgM to promote B cell proliferation.
A typical example is that of B-1 cells isolated from the
peritoneal cavity of normal mice and splenic B cells isolated from newborn mice. Both populations are known to
be unresponsive to IgM cross-linking. The same proved
true upon CD38 ligation. However, signaling through
CD38 and IgM does not always have identical effects on B
cells, since anti-CD38 cannot deliver inhibitory growth or
differentiation signals to normal B cells or immature B
cell lines (223).
The relationship between CD38- and BCR-mediated
signaling was examined in detail in a follow-up paper by
the Maureen Howard group (Palo Alto, CA). Cross-linking
of CD38 and the BCR gave rise to a synergistic response;
moreover, expression of CD38 lowered the threshold for
BCR-induced responses. As a model, the authors then
selected CD38⫹/sIg⫺ cells that were unresponsive to
CD38 signals. Reconstitution with Ig␣ or Ig␤ rescued
CD38 responsiveness, provided that the chimeric molecules were coligated with CD38. Separate experiments
also indicated that the cytoplasmic tail of CD38 is not
required for signaling (224). This last point was confirmed
by the finding that deletion of the cytoplasmic tail and the
transmembrane domains did not impair CD38 signaling,
coreceptor activity, or enzyme activities. Instead, independent point mutations in the extracellular domain of
CD38 dramatically impaired signal transduction. Nevertheless, no correlation was found between CD38-mediated signaling and its enzymatic activity (222). The model
proposed was that CD38 signaling and coreceptor activity
are regulated in vitro by conformational changes induced
in the extracellular domain upon ligand/substrate binding,
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2. Neutrophils
The finding that the loss of CD38 renders mice susceptible to bacterial infections touched off a highly fruitful investigation on the role of CD38 in innate immunity.
It was shown that CD38 KO neutrophils are incapable of
directionally migrating to the site of infection. The molecular basis of this defect lies in that neutrophil chemotaxis
to fMLP is dependent on Ca2⫹ mobilization mediated by
cADPR. Thus CD38 controls neutrophil chemotaxis and
acts as a critical regulator of inflammation and innate
immune responses (271).
3. Dendritic cells
Impaired migration towards sites of immune responses is not unique to CD38 KO neutrophils; it is also a
feature of dendritic cells (DC). Indeed, DC precursors
from CD38 KO mice were unable to migrate from the
blood to peripheral sites, and mature DCs could not migrate from sites of inflammation to the lymph nodes. Thus
T cells are inefficiently primed in CD38 KO mice, leading
to poor humoral immune responses. It was also shown
that CD38 and cADPR modulate Ca2⫹ mobilization in
chemokine-stimulated DCs and that they are required for
the chemotaxis of immature and mature DCs to CCL2,
CCL19, CCL21, and CXCL12. Therefore, CD38 regulates
adaptive immunity by controlling chemokine receptor signaling in DCs (272).
E. CD157
Like CD38, CD157 acts as a receptor able to generate
signals. Early evidence of its receptorial nature derived
from analysis of the BM microenvironment, where the
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molecule is expressed by stromal cells and supports the
growth of a murine pre-B-cell line (175).
The signal-transduction ability of CD157 was analyzed using specific antibodies mimicking the natural ligand, which is yet to be identified. CD157 cross-linking by
a polyclonal antibody induced tyrosine phosphorylation
of a 130-kDa protein in the human myeloid cell lines U937
and THP-1. Instead, cross-linking of CD157 as overexpressed by a mouse transfectant induced tyrosine phosphorylation of p130, dephosphorylation of the 100-kDa
protein, and cell growth inhibition (265). The identification of p130 with the focal adhesion kinase (FAK) is
controversial; indeed, the correspondence has only been
demonstrated in a limited number of cell lines (155, 213).
CD157 regulates calcium homeostasis in human myeloid cells and mediates superoxide production in the
U937 line (164). Recent experimental evidence suggests
that critical functions of human neutrophils are orchestrated by CD157. Indeed, CD157-mediated signals promote cell polarization, regulate chemotaxis induced
through the high-affinity fMLP receptor, and control diapedesis (106, 268). Real-time microscopy revealed that
CD157 engagement leads to a sort of disorientation of
neutrophils, which meander towards the interendothelial
junctions, where they eventually stop without transmigrating. These findings are supported by the observation
that neutrophils obtained from patients with paroxysmal
nocturnal hemoglobinuria (marked by defective expression of GPI-anchored molecules, including CD157) are
characterized by severe defects in neutrophil migration
(268).
Because it lacks a cytoplasmic domain, CD157 must
associate with some professional receptor(s) to compensate for its structural ineptitude to transduce signals.
Recent results suggest that CD157 is functionally and
structurally associated with the CD11b/CD18 complex on
human neutrophils (207).
The relationship between the molecule’s enzymatic
activities and its receptorial functions is an intriguing
issue. CD157-catalyzed generation of extracellular cADPR
is followed by the concentrative uptake of the cyclic
nucleotide by hemopoietic progenitors and may be a potentially relevant step in normal hemopoiesis (282). However, if this is due to the effects mediated by CD157
cyclase, it remains a controversial issue as to whether
CD157 is enzymatically active in physiological situations
or not, as reported by independent groups (154, 361).
However, both CD157 and CD38 catalyze the production
of other metabolites, including nicotinic acid adenine
dinucleotide phosphate and adenine homodinucleotides
(18), whose functional effects are largely unknown in
physiology.
Ample evidence indicated that CD157 is an immunoregulatory molecule in the murine system; indeed, CD157
cross-linking enhanced the proliferative response of
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It has also been shown that loss of PKC activity
blocks CD38-dependent, B cell proliferation, NF-␬B activation, and subsequent expression of cyclin-D2. Because
CD38 cross-linking does not result in the functional phosphorylation of PLC-␥2 nor does it cause an increase in IP3
production, an alternate diacylglycerol-producing phospholipase must participate in CD38 signaling. Consistent
with this idea, CD38 increased the enzymatic activity of
the phosphatidylcholine (PC)-metabolizing enzymes, PCPLC and phospholipase D. The PC-PLC inhibitor D609
completely blocked CD38-dependent B cell proliferation,
IkB degradation, and cyclin-D2 expression. Analysis of
btk mutant B cells demonstrated a partial requirement for
btk in the activation of both enzymes. Taken together,
these data demonstrate that CD38 initiates a novel signaling cascade leading to btk-, PC-PLC-, and phospholipase
D-dependent, PLC-␥2-independent, B lymphocyte activation (248).
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
V. ENZYMATIC ACTIVITIES
A. Historical Perspective
The identification of a sequence similarity between
the human lymphocyte antigen CD38 and the Aplysia
ADPRC (318) marked the beginning of long-term investigations into the enzymatic properties of CD38 and into
their role in human physiology and pathology. Fifteen
years of continuous research have revealed that CD38 is a
multifunctional (ecto)-enzyme that is involved in the catabolism of NAD⫹ and NADP⫹, the two main substrates of
the molecule thus far identified. This reaction leads to the
generation of potent intracellular Ca2⫹-mobilizing compounds (cADPR, NAADP, and ADPR); its main product,
ADPR, can be covalently attached to proteins whereby it
modifies the protein functions. The importance of these
enzymatic pathways has been demonstrated not only in
the immune system, but also in tissues and organs, including uterus, bronchi, pancreas, and kidney (130).
Several issues continue to baffle researchers. Perhaps the most intriguing concerns the relation(s) between
the molecule’s enzymatic and receptorial functions. It is
clear from evolutionary studies that the enzymatic function precedes the receptorial one and that the dual behavior of the molecule is likely the long-term outcome of
selective pressure. If evolution has indeed played such a
role on CD38, particular caution must be exercised when
translating the results obtained in animal models to the
human system. Moreover, all the evidence collected to
date indicates that the receptorial functions are limited to
surface CD38, which is in turn prevalently found in immune cells.
This section provides an overview of the enzymatic
activities mediated by CD38 and CD157 and outlines their
Physiol Rev • VOL
regulation and the main functional models in which they
have been assessed.
B. Enzymatic Activities Controlled by CD38
The enzymatic properties of CD38 were formally
demonstrated after analyzing a purified recombinant soluble form of the molecule. When added to NAD⫹, sCD38
catalyzed the formation and hydrolysis of cADPR (150).
Similar results were obtained using solubilized human
erythrocyte membranes: the three ectoenzyme activities,
i.e., NADase, ADPRC, and cADPR hydrolase, could be
purified to homogeneity using an anti-CD38 monoclonal
antibody (361).
These results were confirmed in human T cell models, where the NAD-hydrolyzing enzymatic activity proved
to correlate with the amount of CD38 on the cell surface.
Moreover, CD38 immunoprecipitated from thymocytes
behaved as an authentic NADase enzyme, by transforming
NAD stoichiometrically into nicotinamide and ADPR
(111) (Fig. 4).
Furthermore, transient transfection of CD38 cDNA in
COS1 cells resulted in the expression of CD38 molecules
capable of converting NAD to cADPR in the extracellular
medium, as assessed by Ca2⫹ release from sea urchin egg
microsomes (321). Further results indicated that cADPR
is a reaction product rather than an obligatory intermediate reaction during glycohydrolase activity (22).
Initially, most research focused on the production of
cADPR, given its central role in cell physiology. Only later
did attention turn to investigation of the various other
enzymatic activities. The soluble extracellular domain of
CD38 was shown to mediate ADP ribosylation of several
proteins, including CD38 itself. This process occurs at
cysteine residues and can be reversed by the addition of
HgCl2, which specifically cleaves thiol-glycosidic bonds
(128). It was suggested that during exposure of activated
T cells to NAD⫹, CD38 is modified by ecto-mono-ADPribosyltransferase (ARTs) specific for cysteine and arginine residues. Arginine-ADP-ribosylation results in inactivation of both the cyclase and hydrolase activities of
CD38, whereas cysteine-ADP-ribosylation leads only to
inhibition of the hydrolase activity. Arginine-ADP-ribosylation causes a drop in intracellular cADPR and a subsequent decrease in Ca2⫹ influx, causing the death of the
activated T cells (134). This is additional evidence that
nucleotide-metabolizing (ecto)-enzymes are not just solo
players, but likely work in a tightly orchestrated and
interchained fashion (64) (Fig. 5).
The role of ADP ribosylation in controlling T cell
homeostasis was subsequently addressed by studying
NAD-induced cell death (NICD). It was shown that extracellular accumulation of NAD induces ADP ribosylation
of the cytolytic P2X7 purinergic receptor. This phenome-
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sorted pre-T lymphocytes to anti-CD3 stimulation and
accelerates the development of fetal thymic organ cultures (342). Moreover, the expression of CD157 by murine
B cell progenitors parallels DJ rearrangement of the immunoglobulin heavy chain genes (165). This suggests that
CD157 plays a role at critical stages of lymphopoiesis,
being implicated in both early T and B cell lymphocyte
growth and development. However, this working hypothesis was not confirmed by the murine KO model, which
demonstrates that CD157 plays a central role in the regulation of humoral T-independent immune responses and
the mucosal thymus-dependent response (164). Indeed,
KO mice showed impairment of thymus-independent antigen-induced IgG3. In addition, oral immunization with
thymus-dependent antigens led to low production of specific IgA and IgG in the fecal extract, due to a reduced
number of antigen-specific antibody-producing cells in
the intestinal lamina propria (166).
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non induced ATP-independent activation and initiated the
apoptotic process (309). The model thus proposed is that
ARTs can sense and translate the local concentration of
ecto-NAD⫹ into corresponding levels of ADP-ribosylated
cell surface proteins, while CD38 controls the level of cell
surface protein ADP-ribosylation by limiting the substrate
availability for ARTs (201). This process is thought to
culminate in selective expansion of primed T cells at the
expense of resting lymphocytes, which are uniquely sensitive to NICD. NICD therefore contributes to the dynamic
regulation of T cell homeostasis (4). In this context, recent studies showed that NAD also acts as a proinflammatory cytokine, stimulating human granulocytes and potentially recruiting them at sites of inflammation (32).
These events are mediated via P2Y11, suggesting a functional interaction between ADPRC (CD38 and CD157) and
purinergic receptors (250).
The role of CD38 in controlling NAD⫹ levels was
further examined by the E. N. Chini group (Rochester,
MN). Shifting the focus from the cell surface to the intracellular compartment, these authors postulated that CD38
is the major NADase in mammalian cells and that it
regulates intracellular NAD⫹ levels (6). In a subsequent
study, the same authors proposed that CD38 could modulate the activity of sirtuins, NAD-dependent deacetylases
implicated in ageing, cell protection, and energy metabolism in mammalian cells. This regulation occurs inside the
nucleus and is mediated by CD38 expressed by the inner
nuclear membrane (5). Recently, the CD38/sirtuin axis
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was reported as playing a major role in the regulation of
body weight in mice (16).
The complex relationships between CD38 and other
NAD-dependent enzymes are illustrated in Figure 6.
A separate enzymatic activity attributed to CD38 involves the catalytic exchange of the nicotinamide group
of NADP⫹ with nicotinic acid (NA). The product is nicotinic acid adenine dinucleotide phosphate (NAADP), a
potent Ca2⫹-mobilizing metabolite (1, 300). This activity
occurs selectively at an acidic pH; the acidic dependence
of NAADP metabolism, coupled with its biological function in targeting the acidic Ca2⫹ stores in cells, suggests
that NAADP serves as a specific Ca2⫹ messenger for the
acidic organelles of the endocytic pathway in cells (210).
There is recent support for NAADP-elicited Ca2⫹ release
from lysosomes and endosomes (241). However, it was
also shown that NAADP can release Ca2⫹ from the endoplasmic reticulum (113, 114).
Thus, in addition to IP3, internal Ca2⫹ stores can be
mobilized by at least two other molecules, cADPR and
NAADP, which target separate Ca2⫹ stores and are bound
by distinct receptors (48, 353). However, these two new
Ca2⫹ agonists are intimately related, since the same enzymes can, under appropriate conditions, synthesize either one. This suggests that a unified mechanism may
regulate both pathways (209) (Fig. 4). The importance of
NAADP as a second messenger was further confirmed in
pancreatic acinar cells, which have properties that make
them particularly attractive for studies of Ca2⫹ signaling
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FIG. 4. The multiple enzymatic reactions catalyzed by CD38. The chemical structures of the substrates and products of the reaction are shown.
(Figure kindly provided by Dr. H. C. Lee, Minneapolis, MN and Hong Kong, China.)
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
859
events initiated by Ca2⫹ release from intracellular stores
(280). In these cells, the hormone cholecystokinin elicits
a mixture of local and global cytosolic Ca2⫹ signals (354).
These signals may be abolished by blocking NAADP receptors. The effect is selective, since inactivation of the
same receptors does not inhibit acetylcholine-induced
Ca2⫹ (35). The conclusions from the studies in the model
are that irrespective of whether the primary stimulus is
acetylcholine, cholecystokinin, or one of the internal messengers, Ca2⫹ spiking can be abolished by either IP3
receptor or ryanodine receptor antagonists. Further studies revealed a functionally important interplay between
IP3, cADPR, and NAADP in the transformation of local
cytosolic Ca2⫹ spikes (via IP3) to global Ca2⫹ transients
(via cADPR and NAADP) (36).
Aplysia ADPRC and CD38 share another enzymatic
activity. They both have the ability to exchange the base
group of NAD⫹ with various nucleophiles, leading to the
formation of a dimeric ADPR (ADPR2). Although ADPR2
did not release Ca2⫹ from sea urchin egg microsomal
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vesicles, it specifically enhanced the Ca2⫹-releasing activity of subthreshold concentrations of cADPR (58).
Recently, the cyclases from lower and higher Metazoa were also found to synthesize diadenosine diphosphate and two of its isomers, all of which are adenylic
dinucleotides from cADPR and adenine. These dinucleotides are present and metabolized in mammalian cells and
influence intracellular Ca2⫹ and cell proliferation (18).
The Ap2A isomer P24 was shown to affect mitochondrial
function, while the other products of ADPRC activity,
namely, Ap2A and cA cDPR, antagonize P24-induced proton gradient dissipation and cytotoxicity. This indicates
that the relative concentration of P24, cADPR, and Ap2A
may rule the balance between cell life and death (30).
Specific attention has recently turned to ADPR. Although it is the main product of the enzymatic activities,
ADPR initially lacked a clear role as an intracellular signaling molecule in vertebrate systems (279). It was later
shown that ADPR activates the melastatin-related transient receptor potential cation channel TRPM2 after bind-
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FIG. 5. Schematic representation of a cell surface membrane expressing a set of functionally related nucleotide-metabolizing cell surface
enzymes. It is still to be defined whether this is a single cell or a microenvironment. The enzymatic functions are functionally linked, and this is
obtained with structural associations and specific localization in membrane microdomains. The ultimate goal is to scavenge nucleotides; however,
the intermediate compounds may act as potent signaling molecules inside or outside of cells.
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CD38/CD157
6. Network between CD38/CD157 and other NAD⫹-metabolizing enzymes.
ing to the Nudix domain. These data revealed that ADPR
and NAD⫹ act as intracellular messengers and may play
an important role in Ca2⫹ influx by activating TRPM2 in
immunocytes (299). Closer investigation showed that
cADPR and NAADP can facilitate ADPR-mediated activation of TRPM2 by lowering its threshold. The mechanism
of action is thought to involve mobilization of ADPR via
metabolic conversion (19, 94, 195). This novel activation
pathway has been studied in Jurkat T cells activated by
high concentrations of concanavalin A, which induced an
increase in ADPR concentration, TRPM2 activation, and,
eventually, cell death (110).
ably increases both the cyclase and hydrolase activities of
CD157, as is the case for CD38. In contrast, Cu2⫹ shows
inhibitory effects on both catalytic activities of CD157,
whereas it increases the cyclase activity of CD38 on the
erythrocyte membrane (142, 362). These discrepancies
may be useful in discriminating between CD157 and CD38
activities and suggest that the enzymatic activity of each
molecule can play distinct roles in different environments.
C. Enzymatic Activities Controlled by CD157
The study of the regulation of the enzymatic activities
of CD38 has been hampered by the lack of specific and
effective inhibitors and by the unexpected finding that
none of the monoclonal antibodies available in mouse
and rat influences the enzymatic activity, either negatively or positively. A recent report shows that a human
monoclonal antibody is endowed with inhibitory potential (320).
Table 3 is a list of compounds and their corresponding regulatory activities on CD38, as known to date and as
Similarly to the Aplysia enzyme and to CD38, soluble
CD157 incubated with NAD⫹ produces cADPR and subsequently ADPR, indicating that this molecule is endowed
with both ADPRC and cADPR hydrolase activities (142,
176). However, the catalytic efficiency of CD157 is several
hundredfold lower than that of CD38 (154).
The enzymatic activities are pH dependent and require metal ions: the addition of Zn2⫹ and Mn2⫹ remarkPhysiol Rev • VOL
D. Regulation of the Enzymatic Activities
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FIG.
861
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
TABLE
3.
Regulation of CD38 enzymatic activities
Compound
Effect
ATRA
Zn2⫹
Serine phosphorylation
Glycosylation
PseudocarbaNAD
DTT
ATP
Gangliosides
Upregulates expression and consequently enzymatic functions
Activates APDRC; inhibits NADase
cADPR overproduction
Diminishes Vmax of ADPRC
Block enzymatic activities of human (not murine) CD38
Blocks enzymatic activities
Selectively blocks cADPR hydrolyzing activity
Selectively blocks NADase activity
D. Functional Models
The finding that the enzymatic site of CD38 is located
outside the plasma membrane raised a number of questions about 1) the accessibility of the NAD⫹ substrate,
which is present only in minute amounts outside the cells,
and 2) the transfer of cADPR to the cytoplasm (57). A
possible solution was proposed based on the finding that
connexin 43 (Cx43) works as a NAD⫹ channel located on
the cell surface (96). Furthermore, it was proposed that
CD38 is an active cADPR pump (97). Subsequent studies
showed that cADPR may be transferred inside the cell
also by nucleoside transporters (NT) (one equilibrative
and three concentrative) (275). The deriving model provides evidence of an extensive trafficking of nucleotides
and their metabolites across the plasma membrane and
likely the membranes of the cytoplasmic vesicles. The
NAD⫹ channels function in a paracrine and in an autocrine way, pointing to the fact that the enzyme activity of
CD38 could be regulated simply by modifying the availability of the substrate.
Thus Cx43⫹ and CD38⫹ cells can provide cADPR to
neighboring RyR⫹ parenchymal cells and enhance their
intracellular Ca2⫹ levels and Ca2⫹-dependent functions
(97). Examples of cADPR-responsive cells via paracrine processes include 1) bovine smooth myocytes (95), 2) murine
fibroblasts (31), 3) rat hippocampal neurons (341), and
4) human hemopoietic stem cells (283).
The role of cADPR as a signaling molecule in T
lymphocytes was investigated by the A. Guse group (Hamburg, Germany). These authors showed causal relations
between the increased concentrations of cADPR, sustained Ca2⫹ signaling, and activation of T cells (131).
These chained effects are directly mediated through
cADPR binding to RyRs (205).
Other groups investigated the role of CD38 outside
lymphocytes. ADPRC activity has been detected in
most cells and tissues, and cADPR is a second messenger involved in most eukaryotic cell functions (209).
Physiol Rev • VOL
198
203
33
42
345
160
327
135, 136
The best studied models include smooth muscle cells of
different origins (vascular, bronchial, and uterine), epithelial cells, and secretory cells (including pancreas,
kidney, and hypophysis). The basic mechanism of action is dependent on the production of cADPR, whereas
the final outcome is dependent on the specific role of
cADPR in the tissue.
1. Myometrium
The CD38/cADPR pathway of intracellular Ca2⫹ mobilization is upregulated in the rat myometrium by estrogens. This process is inhibited by the presence of progesterone. The effects of estrogens on CD38 and on the
differential regulation of its enzyme activities are also
detectable in the myometrium at term. In preterm rat
myometrium, the level of CD38 expression and its enzyme
activities are comparable to those seen in myometrium
obtained from ovariectomized rats or from ovariectomized rats treated with progesterone along with estrogens
(78). The effects on CD38 expression and the differential
regulation of its enzyme activities seem to favor cADPR
production, cADPR-induced Ca2⫹ release, and increased
contractility of the myometrium. It has recently been
demonstrated that the cADPR system is important in
oxytocin-induced Ca2⫹ transients in human myometrial
cells (15). This suggests that cADPR may be an endogenous regulator of the Ca2⫹-induced Ca2⫹ release mediated through RyR in human myometrial cells and may
play an important role in successful delivery (44, 79).
2. Smooth muscle cells
CD38 expression in airway smooth muscle cells contributes to the contractile response in the bronchi and is
tightly regulated at a genetic level. This finding is particularly relevant for pathological conditions such as asthma,
where proinflammatory cytokines induce CD38 expression and glucocorticoids attenuate it. This may prove
clinically relevant in the treatment of asthma (76).
The expression and function of CD38 has been evaluated in several other smooth muscle cell models, including peritubular (17) and vascular (61) muscle cells.
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referred in References 33, 42, 135, 136, 160, 198, 203,
327, 345.
Reference Nos.
862
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3. Bone metabolism
VI. ANIMAL MODELS
Animal models deficient or hyperexpressing a single
molecule have in many instances been fundamental tools
for understanding its biological role in the murine and
likely the human system. The underlying assumption is
that if a protein exerts a nonredundant function, then its
complete lack will result in the complete loss of that
function. This has been the first problem with the CD38
KO mice. Indeed, these animals show an almost complete
loss of tissue-associated NADase activity, with a significant reduction of cADPR values (43, 49, 357). Accordingly, NAD⫹ levels are altered in multiple tissues, even
though the physiological consequences are still to be
determined.
Moreover, cADPR loss however is not complete, suggesting that CD157 and/or yet unidentified members of the
family may compensate for the absence of CD38. A double CD38/CD157 KO has not yet been published, somewhat preventing general conclusions.
The CD38 KO mice are viable and appear to breed
normally, leading to the conclusion that CD38 and its
enzymatic activities are not necessary for life. Further
examination of these mice confirmed that the development of the hematopoietic lineages is not influenced by
the absence of CD38. On the contrary, the molecule is
required for optimal T cell-dependent humoral immune
responses (49). In later reports, the F. Lund group (Saranac Lake, NY) extended the analysis of the immune system of these animals under stressful conditions, including
bacterial infections. Loss of CD38 renders mice susceptible to bacterial infections due to an inability of CD38 KO
neutrophils to migrate to the site of infection (271). When
infected with the gram⫹ organism S. pneumoniae, CD38
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The M. Zaidi group (New York, NY) conducted extensive studies on the expression and function of CD38 in
osteoblasts and osteoclasts of different species. They
found that the molecule is expressed by both cell types in
different cellular compartments, including the nucleus. In
addition, they showed that CD38 activation in the osteoclast triggers Ca2⫹ release, stimulates the production of
IL-6, and inhibits bone resorption (2, 322). Consistent with
these findings, CD38 KO mice displayed strikingly reduced bone mineral density at 3 mo, with full normalization at 5 mo. Hematopoetic stem cells isolated ex vivo
from CD38 KO mice showed a dramatic, approximately
fourfold increase in osteoclast formation (323). Furthermore, cADPR or exogenous addition of ADPRC stimulated osteoclast formation. Conversely, blocking cADPR
action with the analog 8-bromo-cADPR strongly inhibited
osteoclast formation. These effects seem to be predominantly related to the NADase activity of CD38 (162).
KO mice upregulated normally the expression of inflammatory cytokines systemically as well as in the lung.
However, the inflammatory cell infiltrate was significantly
reduced in the lungs of these mice, and the bacteria
rapidly disseminated from the lungs to the blood, causing
death within 36 h in the majority of the animals (271). The
defect can be attributed to the lack of cADPR, which
directly induces intracellular Ca2⫹ release in wild-type
neutrophils and is required for sustained extracellular
Ca2⫹ influx in neutrophils that have been stimulated by
fMLP, a bacterial chemoattractant (271). Likewise, CD38
KO neutrophils are unable to migrate in response to several endogenous chemoattractants and chemokines, including serum amyloid A and MIP-1␣ (273).
The first conclusion is that CD38 controls neutrophil
chemotaxis to bacterial chemoattractants through the
production of cADPR. This concept was further strengthened by successive studies on DC. Indeed, CD38 regulates
migration of DC precursors from the blood to peripheral
sites and controls the migration of mature DCs from sites
of inflammation to lymph nodes. The consequence for the
immune response is that T cells are inefficiently primed in
CD38 KO mice, leading to poor humoral immune responses. The molecular mechanism relies on the lack of
cADPR, which is required for the chemotaxis of immature
and mature DCs to CCL2, CCL19, CCL21, and CXCL12
(272).
The first interest in generating animals overexpressing or lacking CD38 was linked to the proposed model of
NAD⫹ as a central agent in the pathogenesis of pancreatic
␤-cell damage and consequent onset of diabetes. The
Okamoto group designed a model of insulin release and
pancreatic ␤ cell damage based on a complex interplay
between NAD⫹, PARPs, CD38, and cADPR. To confirm
this model, the authors initially prepared mice overexpressing CD38 and showed that the transgenic serum
insulin level was higher than that of control in glucosetolerance tests, suggesting enhanced release (179). The
general inference is that Ca2⫹ release from intracellular
cADPR-sensitive Ca2⫹ stores and the Ca2⫹ influx from
extracellular sources plays important roles in insulin secretion (179). The experiments conducted later by generating CD38 KO mice highlighted impaired glucose tolerance, with serum insulin levels lower than controls. The
pathological phenotype was rescued by ␤ cell-specific
expression of CD38 cDNA (180).
The interest on diabetes was recently continued by
showing that CD38 KO islets are significantly more susceptible to apoptosis compared with islets isolated from
littermate controls. The conclusion of these experiments
is that CD38 plays a role in novel antiapoptotic signaling
pathways, but does not directly control glucose signaling
in pancreatic ␤-cells (173).
The observations brought about in the genetically
modified animals were assessed in spontaneous disease
863
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
TABLE
4.
tile agonists (129). Other districts concern smooth muscle
in heart (324) and vessels (243).
There is still an enormous amount of data derived
from the use of CD38 KO mice waiting to be organized for
publication. A number of papers report on data inferred
by using KO mice: other ones concern the role of CD38 in
bone (323) and fat control (16). Table 4 tries to comprehensively summarize the majority of published reports.
The experience using CD157 KO mice is more limited. The phenotype of the animals is characterized by a
partial impairment of thymus-independent and thymusdependent antigen-specific immune responses. Oral immunization of CD157 KO mice with cholera toxin, a potent thymus-dependent antigen for the induction of IgA
response, resulted in the poor production of specific antibodies at the intestinal mucosa accompanied by reduced
numbers of IgA-producing cells in the LP. These results
suggest that CD157 has roles in B cell development and
antibody production in vivo (166) (Table 4).
VII. PHYLOGENY AND GENE ORGANIZATION
A. From One Soluble Gene to a Family
of Transmembrane Proteins
NADase/ADPRC enzymatic activities are found in
bacteria (29, 186), plants (347), and metazoans (297). The
eukaryotic NADase/ADPRCs form a unique gene family of
very small size, which makes it convenient when cataloguing new members as orthologs (same gene, different
species) or paralogs (genes related by duplication). From
Phenotypes of the CD38 and CD157 knockout mice
System/Organ
CD38
Immune system
Pancreas (␤-cells)
Strain
Defect
C57BL/6
2 Antibody responses to T cell-dependent
antigens
Impaired neutrophil chemotaxis
Impaired dendritic cell chemotaxis
1 Apoptosis, 2 insulin secretion
2 CD8⫹ T cells, impaired Treg development,
1 apoptosis of iNKT cells
Normal glucose receptor signaling, but
increased apoptosis
1 Osteoclast formation
2 Smooth muscle contractility
C57BL/6
C57BL/6
ICR
NOD/Lt
C57BL/6
Bone
Lung
C57BL/6
C57BL/6
Heart
Aorta
Fat
ICR
ICR
C57BL/6
Brain
CD157
Immune system
ICR
C57BL/6
Outcome
Altered myocyte contractility
2 Contractility
Regulation of mitochondrial biogenesis and
energy homeostasis
2 Oxytocin release
Delayed development of B-1 cells, altered Ig
responses
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Reference Nos.
2 IgG titers
49
1 Death by infection
1 Death by infection
Impaired glucose tolerance
1 Autoimmune diabetes
271
272
180
38
No impairment in glucose tolerance, no
diabetes
2 Mineral density
Constitutively impaired airway responsiveness
and impaired airway responsiveness in
response to IL-13 challenge
Cardiac hypertrophy in male
2 ␣-Adrenoreceptor-induced contraction
2 High-fat-diet-induced obesity
40
323
76
324
243
16
Altered short-term social memory
172
Altered B cell homeostasis
166
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models of autoimmune type 1 diabetes, typically of the
NOD strain. The onset of diabetes is significantly anticipated in the CD38 KO NOD/Lt mice, due to an impairment
of both the regulatory T cell compartment and of the
invariant NKT (iNKT) cells. The molecular mechanisms
remain partially unknown, even though an interplay between CD38 and ART2 is hypothesized (38, 40).
A role for the CD38/cADPR system in regulating hormone secretions has very recently been proposed by the
Higashida group. By observing adult CD38 KO female and
male mice, the authors were able to highlight marked
defects in maternal nurturing and social behavior, respectively. This correlated with higher locomotor activity,
while plasma levels of oxytocin (OT) were strongly decreased in CD38 KO mice. Surprisingly, vasopressin was
unaffected in the model. The group went on to show
impaired OT release in the CD38 KO mice, which could be
reverted by genetic reconstitution of CD38 expression in
the neurohypophysis. These results reveal that CD38 has
a key role in neuropeptide release, thereby critically regulating maternal and social behaviors, and may be an
element in neurodevelopmental disorders (141, 172).
The other area of interest concerns the role of CD38
in smooth muscle contraction in distinct organs and tissues. In the lung, the CD38/cADPR system contributes to
airway smooth muscle tone and responsiveness through
its effects on agonist-induced elevation of intracellular
Ca2⫹ (76). This model was further expanded by examining the effects on lungs exposed to IL-13, a cytokine
involved in the pathogenesis of asthma. Under these conditions, CD38 contributes to airway hyperresponsiveness
by increasing airway smooth muscle reactivity to contrac-
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MALAVASI ET AL.
Physiol Rev • VOL
and their effects on protein dynamics provide an explanation for how the vertebrate enzymes reached the cell
surface. On the contrary, the sectorial distribution of the
metabolic effects to within cellular organelles may help to
explain why.
A working hypothesis is that early CD38/CD157 precursors are part of the innate immunity, and their passage
to the surface of immune cells may have gone in parallel
with the transition to adaptive immunity.
It would be nice to find evidence that the first lymphocytes of the vertebrate protoimmune system to
emerge in some primitive jawed fish over 500 mya expressed a NADase/ADPRC on their surface. Indeed, the
first in silico evidence of a tandem duplication of NADase/
ADPRC genes comes from Tetraodon negroviridis.
In conclusion, the CD38 and CD157 genes are duplicates, and as such, at least one copy could have undergone pseudogenization and disappeared without trace.
They have survived with modification to join the ranks of
genes pertaining to chemosensation, immunity, and reproduction, those most frequently duplicated during
mammalian evolution (Fig. 7).
B. Structure and Organization of CD38
and CD157 Genes
The CD38 gene is localized on the short arm of
chromosome 4 (4p15) (169, 259). The CD38 polypeptide is
encoded by a ⬎80 kb gene, more than 98% of which is
represented by intronic sequences. The gene has eight
exons, and exon 1, the largest coding exon, determines
the intracytoplasmic and transmembrane regions and the
membrane proximal 33 amino acids of the extracellular
region (91, 93).
Control of human CD38 expression appears to be
multitiered. The first level of control lies in the 5⬘-flanking
promoter region of the gene, which with no TATA box
and the presence of a CpG island, resembles many noninducible housekeeping genes. The island is ⬃900 bp
long, encompasses exon 1 and the 5⬘-end of intron 1, and
contains a binding site for the transcription factor Sp1,
suggesting that methylation may intervene in the process
of CD38 gene regulation (92).
A second level of control involves trans-interactions
with sequences that lie further upstream from the transcription start site. Potential binding sites have been identified for the T cell transcription factor-1␣ (TCF-1␣),
nuclear factor for interleukin-6 (NF-IL-6), interferon-responsive element-1 (IRF-1), and binding sites for glucocorticoid
hormones. A third level of control is located at the 5⬘-end
of intron 1 and is involved in the induction of CD38
expression by retinoids in myeloid cells (188) via a retinoic acid-responsive element (RARE).
CD38 has a well-characterized single-nucleotide polymorphism (SNP) located at the 5⬘-end of this intron (184
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sea slug to schistosome, sea urchin, chicken, mouse, macaque, and human, all of the NADase/ADPRC genes derive
from a common ancestor. At the moment, the oldest,
well-characterized NADase/ADPRC gene belongs to Aplysia, whose origins date back to the Cambrian period over
500 million years ago (mya). The compact 8-exon, 7-kb
gene had reached 90 kb by the time humans evolved,
essentially through expansion of the intervening sequences.
Mammals have two NADase/ADPRCs identified as
CD38 and CD157. Their genes are very similar in intronexon structure and reflect their common origins with the
Aplysia ADPRC gene. Arranged head-to-tail in tandem on
Homo sapiens (HSA) chromosome 4 (telomere 3 CD157 3
CD38 3 centromere) and Mus musculus (MMU) chromosome 5, CD38 and CD157 are clearly derived by gene
duplication (92). Analysis of the chicken genome databases and our unpublished data confirm that orthologs of
CD38 and CD157 lie in tandem on Gallus gallus (GGA)
chromosome 4 (E. Ferrero, unpublished data). The presence of both CD38 and CD157 in the chicken genome
indicates that gene duplication predated the reptile/mammal separation over 300 mya.
The products of the NADase/ADPRC genes are either
soluble (e.g., Aplysia and sea urchin) or membranebound enzymes [schistosome (NACE) and CD38 ⫹ CD157
in mammals]. These proteins range in size from the soluble 29-kDa Aplysia ADPRC to the 45-kDa membrane glycoproteins CD38 and CD157. Their stringent conservation
of the three-dimensional structures owes much to the 10
cysteine residues as well as to the inter-cysteine spacing
(216, 284).
Aplysia cyclase shares 25–30% of its amino acid sequence with the CD38 and CD157 polypeptides, but it is
the modifications of the NH2 and COOH terminals which
determine protein topology and localization. The short
NH2-terminal hydrophobic tract found in Aplysia cyclase
is longer in CD38, the result of a process simply requiring
the addition of a few amino acid residues to produce a
type II membrane protein with an NH2-terminal transmembrane domain. The fate of most type II proteins is
associated with the plasma membrane, Golgi apparatus,
and endoplasmic reticulum (ER) (11). This is also the
case with CD38, which thus became an ectoenzyme during its long course through evolution.
CD157 devised a more innovative mechanism for
acquiring membrane attachment. With an NH2-terminal
ER-targeting signal peptide in place, membrane binding
was acquired through the addition of a ninth exon whose
sole raison d’être is to encode a COOH-terminal hydrophobic stretch, which is subsequently removed upon addition of the GPI anchor. The process generated a membrane-bound, GPI-anchored NADase/ADPRC.
The microevolutionary processes that designed the
modifications of the vertebrate NADase/ADPRC genes
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
865
C3 G), which leads to the presence (or absence) of a Pvu
II restriction site (92). The frequency of the three genotypes has been established in healthy Italian-born adults
as 70% CC, 26% CG, and 4% GG. Similar frequencies have
been reported in Spanish (125) and Irish (84) populations.
The SNP is located in an intronic hot spot, containing part
of the CpG island ⫹ RARE mentioned above. In addition,
evidence based on a novel truncated CD38 mRNA transcript suggests that a further mechanism for controlling
CD38 gene expression involves transcriptional elongation, where a stop-or-go decision is taken within the 5⬘end of intron 1 (E. Ferrero, unpublished data).
CD157 extends over 35 kb and consists of nine exons
(255). CD38 and CD157 are highly conserved as demonstrated by the fact that exons 1– 8 are similar in length and
maintain the same phase of intron insertion. As described
above, exon 9 of CD157 encodes the GPI anchor signal
(Fig. 8).
Physiol Rev • VOL
VIII. HUMAN DISEASE MODELS
The study of disease models has been fruitful in
revealing vital immune mechanisms. As a direct consequence, an increasing number of CD family members have
been implicated in the pathogenesis of diseases or as
markers of their prognosis and progression. The CD38
family is no exception. Analysis of CD38 expression is
currently used for the diagnosis of leukemia and myeloma, and the molecule is also used as a powerful independent prognostic marker for CLL patients. Moreover,
CD38 expressed by CD8⫹ and CD4⫹ cells constitutes a
very reliable, economic, and easy-to-use prognostic tool
for the progression to AIDS in HIV-infected patients. Additionally, functional impairment of the CD38/cADPR system has been associated with the disordered insulin metabolism typical of type II non-insulin-dependent diabetes
mellitus (NIDDM).
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FIG. 7. Cladogram illustrating the phylogenetic distribution of ADPRC family members which have been identified either 1) by gene cloning (for
Aplysia gene reference, see Ref. 258; for Schistosome NACE, see Ref. 126; for sea urchin, see accession numbers ABQ09453–5, NCBI; for bovine
CD38, see Ref. 12; for rabbit CD38, see Ref. 3), 2) by homology searches in silico (for fish, frog, platypus, opossum, and other noncloned mammalian
cyclases, see www.ensemble.org), or 3) by the detection of a cADPR-producing enzymatic activity (for Axinella, see Ref. 363; for shark, see Ref.
89). Species have been grouped arbitrarily into invertebrates (orange box), fish (blue), amphibians (green), birds (yellow), and mammals (purple).
866
MALAVASI ET AL.
Here, we focus on the involvement of CD38 in
NIDDM, HIV infection, and CLL, both as a marker and as
a pathogenetic agent. Not analyzed are the recent results
reported by the H. Higashida group, which promise to
open an exciting new field concerning the link between
CD38 and behavior. Extensive analysis in CD38 KO mice
led the authors to conclude that CD38 plays an indirect
role in influencing short-term social memory, mediated
through an impaired release of OT (172). The impact on
human medicine is still to be explored.
A. Diabetes
The earliest report of involvement of the cADPR axis
in insulin metabolism came from experiments using a
cell-free system of islet microsomes. In this model,
cADPR induced Ca2⫹ release, whereas IP3 did not. Moreover, cADPR and Ca2⫹ both induced insulin secretion in
digitonin-permeabilized islets, but IP3 did not. These results suggested not only that cADPR helps mediate Ca2⫹
release from islet microsomes, but that cADPR might be
generated in islets by glucose stimulation, thus serving as
a second messenger for Ca2⫹ mobilization in the endoplasmic reticulum (326).
An independent paper reported on the cloning of a
rat CD38-homologous protein, expressed in pancreatic
islets. Rat CD38 is highly homologous to the human molecule, exhibiting 58% overall identity and 76% similarity
and is expressed at comparable levels in Wistar rats and
GK rats (a genetic model of NIDDM). The presence of rat
CD38 in the pancreatic islets suggested that it is involved
in insulin secretion by synthesizing cADPR (212).
Further studies on GK rats provided the first accepted link between CD38 and diabetes. It was observed
that CD38 mRNA levels are reduced by ⬃50% in islets
Physiol Rev • VOL
(236); in fact, the cADPR signal system for insulin secretion is replaced by IP3 in these islets. It was later seen that
the microsomes in the diabetic ␤-cells release Ca2⫹ in
response to IP3 but not to cADPR. In addition, they overexpress IP3 receptor mRNAs (325).
Later studies exploring the role of the CD38/cADPR
axis exploited animals genetically modified to express
either high or low amounts of CD38. More specific information concerning the effects of the overexpression or
deficiency of CD38 is reported in the relevant sections.
Generally speaking, however, it can be said that mice
overexpressing CD38 exhibit enhanced glucose-induced
insulin release, while CD38 KO mice display severe impairment of ␤ cell function.
A report from the Okamoto group on human diabetes
revealed that 13.8% of Japanese NIDDM patients have
autoantibodies against CD38; moreover, sera containing
such autoantibodies inhibited the ADPRC activity of
CD38. The addition of NIDDM sera containing anti-CD38
antibodies to cultured rat pancreatic islets significantly
inhibited insulin secretion induced by glucose, whereas
recombinant soluble CD38 abolished this effect. These
results strongly suggested that the presence of anti-CD38
autoantibodies in NIDDM patients may be one of the
major causes of impairment in the secretion of glucoseinduced insulin (159).
The presence of anti-CD38 autoantibodies was confirmed in Caucasian diabetic patients. High anti-CD38 autoantibody titers were found in 9.7% of type 2 diabetic
patients (231). Another study by the same authors also
revealed anti-CD38 autoantibodies in 13.1% of type 1 diabetes (DM1) patients (286). Anti-CD38 autoimmunity defines a clinical phenotype similar to nonautoimmune type
2 diabetes, with relatively preserved ␤-cell function and
low genetic influence (10). A more recent study reported
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FIG. 8. Schematic representation of
the human CD38 gene. The orange rectangles identify the single exons. The pink
oval depicts the CpG island. The yellow
circles indicate specific responsive elements in the regulatory region of the
gene. The blue pentagons indicate regulatory interleukins for which no responsive element has been identified (the
small arrows indicate whether they exert
up- or down-modulatory effects). The black
diamond highlights the polymorphic site.
ER, estrogen-responsive element; IRF, interferon-responsive element; RARE, retinoic acid-responsive element; TSSs, transcription start sites (indicated by the big
arrows); E2, estrogen; SNP, single nucleotide polymorphism; RAR, retinoic acid
receptor.
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
B. HIV Infection
The expansion of the CD8⫹/CD38⫹ lymphocyte subset was an early alteration frequently observed prior to
the detection of antibodies against HIV and diminished
levels of CD4⫹ cells in subjects at risk of developing
AIDS. An increase in the number of HLA class II⫹, CD38⫹,
and Leu-8⫺ CD8⫹ lymphocytes was associated with a
decline in the number of CD4⫹ cells and development of
the disease (119). Subsequent studies by independent
groups confirmed this observation (349). These pioneer
works disclosed a stage-associated pattern of HLA class II
and CD38 expression on CD8 T lymphocytes during HIV
infection (182). However, it remained unclear as to
whether specific phenotype patterns could have a resulting functional correlation in the host response to the
virus. Indeed, it later turned out that CD8⫹/HLA class
II⫹/CD38⫹ cells exhibited higher HIV-specific CTL activity
than other CD8⫹ cells, indicating that CD38 is expressed
in vivo on virus-specific CD8⫹ CTL (143).
These findings led to several multicenter studies
aimed at determining whether the CD8⫹/CD38⫹ cell subPhysiol Rev • VOL
set had prognostic value for progression to AIDS. They
concluded the following:
1) The percentage of CD8⫹/CD38⫹ cells marks disease progression towards the development of AIDS, independently of CD4 count and ␤2m levels (219, 245). The
Multicenter AIDS Cohort Study confirmed that the elevated expression of CD38 on CD8⫹ T cells is a more
reliable marker for the risk of chronic HIV disease progression to AIDS and death than CD4⫹ cell count, soluble
immune activation markers, or combinations of HLA class
II and CD38 expression (218). The finding that the percentage of activated CD8⫹ cells expressing CD38 can
predict the rate of decline of CD4⫹ T cells before it
becomes clinically relevant is relevant for the disease.
Furthermore, early identification of the CD4⫹ T cell slope
will allow clinicians to target treatment to those patients
who are most likely to benefit (25). This assay was therefore deemed to be potentially useful, in conjunction with
blood CD4 counts and serum ␤2m levels, in patient management and clinical trial design.
2) The test can be performed either on fresh or
frozen cells with identical results (278).
3) The evaluation of CD38 expression on CD8 cells is
a rapid, simple, and economical method of studying HIV
infection and progression to AIDS. Not less important is
the fact that such a low-cost test may result in wide
application in developing countries, generally burdened
by high rates of disease (267).
4) In children, too, expression of CD38 on CD8⫹ T
cell predicts maintenance of high viremia in highly active
anti-retroviral treatment (HAART)-treated HIV-infected
patients (311, 343). This is consistent with the view that
increased CD38 expression on CD8⫹ T cells has the same
prognostic significance in pediatric as in adult HIV disease.
5) High numbers of CD38⫹/CD8⫹ cells may indicate
an underlying chronic but blunted activation, which is
ultimately unable to control disease progression (121).
Indeed, profound CD8⫹ cell activation was seen in all
subjects at seroconversion and at 6 and 12 mo later. The
CD8⫹/HLA class II⫹/CD38⫹ cell population, which has
potent direct HIV cytotoxic T cell activity, was markedly
elevated at seroconversion. In individuals that maintained
high HLA class II⫹/CD38⫺/CD8⫹ expression throughout
the first year of infection, CD4⫹ cell counts were stable
during the next 5 yr. Long-term survivors also had elevated levels of this subset, despite the paucity of other
activated CD8⫹ cells. Thus selective elevation of HLA
class II⫹/CD38⫺CD8⫹ cells proved to be a marker of
subsequent stable HIV disease (120).
The issue has recently been taken up again, after a
study revealed that the distribution of HIV-specific CD8⫹
T cells was heavily skewed toward CD38⫹/CD8⫹ T lymphocytes. However, a significant percentage of this subpopulation underwent spontaneous/Fas-mediated apopto-
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elevated anti-CD38 autoantibody titers in 4.4% of children
with DM1. In terms of phenotype, no statistical differences were observed between the anti-CD38 positive and
negative patients. However, a positive correlation was
found between the antibody titers of diabetic sera at
diagnosis and follow-up, suggesting that an autoimmune
reaction against CD38 is associated with newly diagnosed
DM1. CD38 autoimmunity increases over time and persists in children with DM1 (285).
In contrast to the sera in the Japanese survey, a
subset of anti-CD38⫹ sera from Caucasian patients displayed agonistic properties for human pancreatic islets
and led to Ca2⫹ mobilization and insulin secretion (9).
The in vitro agonistic properties of anti-CD38 autoantibodies may also be at play in vivo, as they identify subgroups of patients with higher residual ␤-cell function
(231). In the long run, however, culture of ␤-cells with
anti-CD38⫹ sera leads to functional impairment and compromised viability (233).
A study of Japanese type 2 diabetes patients with
first-degree and/or second-degree relative(s) having the
same disease revealed a mutation in the third exon of the
CD38 gene in a limited number of patients (4/31). The variant
in exon 3 resulted in an amino acid substitution from
Arg-140 (CGG) to Trp (TGG), followed by an ⬃50% reduction of ADPRC and cADPR hydrolase activities (350). This
mutation was not seen in Caucasian patients (230), nor
was preferential distribution of the CD38 alleles found in
diabetic patients (230).
It should be noted, however, that a recent study using
liquid-phase methods failed to detect binding of autoantibodies to recombinant CD38 in diabetic patients (316).
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confers partial protection against acute cell death from
HIV to CD38low cell lines. Nicotinamide may thus be at
least partially responsible for the correlation observed
between high levels of CD38 and low rates of acute cell
death from HIV (306). A follow-up paper reported that
CD38 expression is negatively correlated to susceptibility
to HIV infection, likely because of interference with
gp120/CD4-dependent viral binding to target cells (304).
This is due to strong lateral associations between CD38
and the HIV receptor CD4. The association is further
accentuated by the HIV envelope gp120 glycoprotein. According to this model, CD38 prevents HIV infection by
specifically inhibiting gp120/CD4 binding. The anti-HIV
activity exerted by CD38 was mapped in the membraneproximal region, which displays significant sequence similarity with the V3 loop of the HIV gp120 glycoprotein.
Similar effects were obtained by using synthetic soluble
peptides derived from this region, reproducing the antiHIV effects of full-length CD38. Moreover, the same peptides inhibited primary HIV-1 and HIV-2 isolates from
different subtypes and with a variety of coreceptors (303,
305).
Another independent study showed a link between
the susceptibility of CD4⫹ T cells to different strains of
HIV and their surface expression of CD38 (148). However,
the T-tropic HIV proliferated in vitro more efficiently in
the CD4⫹/CD38⫹/CD62L⫹ subset than in the CD38⫺ counterparts. A likely explanation is that the CD4⫹/CD38⫹/
CD62L⫹ subset secretes endogenous Th2 cytokines (e.g.,
IL-4), which promote efficient production of T-tropic HIV
through upregulation at a certain stage of the viral life
cycle, probably after the adsorption step (147).
C. Chronic Lymphocytic Leukemia
The original observation linking CD38 expression to
prognosis in CLL patients was published in a seminal
work by the N. Chiorazzi group (New York, NY) (55). The
authors suggested that CLL cases could be divided into
two groups with prognostic implications according to the
mutational status of their IgV genes. Patients with unmutated IgV genes presented with a more aggressive disease
from diagnosis, had a shorter time to therapy, and ultimately died sooner. The same subset also displayed
higher percentages of CD38⫹ CLL cells, raising the possibility that CD38 could be used as a surrogate marker for
the absence of IgV mutations. This observation was confirmed by many groups operating in different institutions
and clinical centers. A general conclusion from all these
studies is that CD38 expression is a reliable negative
prognostic marker for CLL patients (52, 75, 81, 85, 158,
170, 246, 247). The second conclusion is that the association between IgV mutational status and CD38 expression
is less stringent than originally believed. Both parameters
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sis, indicating that a substantial proportion of the HIVspecific CD8⫹ T cells arise from HIV-driven aberrant
immune activation. The absence of effective cytolytic activity by these cells against infected targets could be
related to their high susceptibility to apoptosis. This
would explain why HIV is not successfully contained by
CD8⫹ T cells in such patients (47). It would seem that an
analogous situation occurs in the CD4 compartment,
where a population of highly activated cytotoxic effector
CD4⫹/CCR5⫹/CD38⫹ cells is expanded immediately after
HIV infection. These cells are prone to both apoptosis and
cytopathic infection by HIV, and rapidly decline (358).
Studies of CD4 cells expressing CD38 also showed
that the number of cells expressing both markers dependably anticipates the clinical signs of progression to AIDS
(183).
Researchers and clinicians also asked whether the
number of CD38⫹/CD8⫹ cells could be predictive of response to therapy. HAART was followed by a rapid decline in CD8⫹/CD38⫹⫹ lymphocytes in parallel with viral
load, allowing for rapid normalization of CD8⫹/CD38⫹⫹ T
cell numbers. This might indicate that CD38 is a marker of
residual viral replication when the viral load falls below
detectable levels following HAART intervention (335).
Likewise, children with high CD38 levels in CD8⫹ T lymphocytes had a higher incidence of and relative risk for
virological failure than did those with low CD38 expression. This means that CD8⫹/CD38⫹ T cell count is a
dependable marker of therapeutic failure in HIV-infected
children (20, 293).
Deciding on the best method for measuring CD38
expression has been the subject of lengthy debate. In
general, CD38 can be quantified by using either QuantiBRITE beads or CD4 expression on CD4⫹ T lymphocytes as calibrators (152, 168, 211). The most recent evidence is that combining measurement of CD38 expression on peripheral blood monocytes with measurement of
CD8⫹ and CD4⫹ T cells is more useful for monitoring
HIV-infected patients under HAART than measurement of
CD38 expression on CD8⫹ T lymphocytes alone (8).
The main issue still to be resolved concerns the
biologic role of CD38 in CD8⫹ T lymphocytes in HIVinfected individuals. What is known is that CD38 is expressed in its fully active form when upregulated on T
cells from HIV patients. The increased expression of
CD38 on lymphocytes during the chronic phase of HIV
infection potentially compensates for the impaired capacity of cells to synthesize ribonucleotides de novo (26).
Also known is the negative correlation between the
levels of surface CD38 expression and the rate of acute
cell death from HIV observed 96 h after infection. This
implies that high CD38 expression correlates with resistance to HIV infection, leading to a lower rate of cell
death. This assumption is further supported by the observation that nicotinamide, a reaction product of CD38,
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
Physiol Rev • VOL
More recently, the cytoplasmic kinase ZAP-70 has
been identified as a further independent negative prognostic marker (50). Thus aggressive CLL can be identified
by absence of mutations in the IgV genes and by the
presence of both surface CD38 and intracellular ZAP-70.
Preliminary results indicate that a combination of CD38
and ZAP-70 provides better identification of high risk CLL
patients (54, 74, 153, 307). The CD38⫹/ZAP-70⫹ subset
also appears to be genetically distinct (156, 277). The
clinical indication that combined expression of CD38 and
ZAP-70 more accurately identifies high-risk patients
prompted us to evaluate the existence of a functional link
between the two molecules in neoplastic B cells. CD38
engagement leads to a transient but significant tyrosine
phosphorylation of ZAP-70 in CD38⫹/ZAP-70⫹ CLL cells.
Furthermore, ZAP-70 expression seems to be a limiting
factor for CD38-mediated functions. Extensive analysis of
CD38 signals proved that the CD38 pathway is selectively
active in CD38⫹/ZAP-70⫹ cells. This observation is clinically relevant because it provides a molecular rationale
for simultaneous testing of CD38 and ZAP-70 for the risk
stratification of patients (70). The question that remains
to be answered is where the CD31/CD38/ZAP-70 axis
leads. The first possibility is that CD38 and ZAP-70 somehow synergize with (or add to) the signals mediated by
the B cell receptor (BCR). Independent studies have
shown that BCR cross-linking results in ZAP-70 activation
and, ultimately, in a stronger signal (39). According to this
line of thinking, CD38 might exert a coreceptorial function, further sustaining the signal mediated by the BCR.
The second possibility is that the presence and functions
of ZAP-70 are linked to the signaling pathways controlled
by CXCR4, CXCR3, and CCR7. Chemokines are reported
to significantly contribute to the delivery of growth signals to CLL cells expressing functional receptors. Indeed,
results obtained in T cell models indicate that the signaling pathway driven by CXCR4 involves ZAP-70 (270, 276).
In support of this view is evidence that ZAP-70⫹ CLL cells
migrate better in response to CXCL12 (294).
Other results obtained using mature dendritic cells
indicate that CD38 engagement ensures efficient chemotaxis in response to CCL21. Additionally, the presence of
lateral associations between CD38 and the CCR7 receptor
may help in fine-tuning cell motility (98). Another report
shows that cADPR antagonists block chemotaxis of human monocytes to CXCR4, CCR1, and CCR5 (273).
IX. THERAPEUTIC APPLICATIONS
The peculiar pattern of cell surface expression of
CD38 made it attractive for the design of therapeutic
protocols driven either by cells or by monoclonal antibodies. In both cases, de novo expression of the molecule is
considered a useful asset for improving the efficacy and
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are now considered independent prognostic markers.
This issue was initially discussed by the T. J. Hamblin
group (Southampton, UK) (132) and later confirmed by
others (171, 234, 334). CD38 was thus seen to be an
independent risk factor that can be used together with IgV
mutation and clinical staging to identify CLL patients with
the poorest prognosis (133). Furthermore, CD38 expression positively correlates with all of the other negative
prognostic markers examined, including cytogenetic abnormalities (202, 269), soluble CD23, soluble ␤2m (138),
p53 function (41, 214), and cell size (232). However, CD38
does not appear to be a prognostic marker in the context
of familial CLL cases (163).
Notwithstanding the impressive number of patients
studied, there is still no generally accepted standardized
procedure for determining CD38 expression. As a consequence, there is no clear threshold above which CD38 is
said to be positive (28, 112, 333). The F. Caligaris-Cappio
group (Milan, Italy) has proposed that it is the presence of
a distinct CD38⫹ population within the leukemic clone
that correlates with IgV mutational status, rather than a
fixed numerical cut-off. Notwithstanding its size, the
CD38⫹ population identifies CLL patients who will have
progressive disease (118).
Other issues to be resolved concern 1) the stability of
CD38 expression over time, which some investigators
think can change over time and in response to therapy
(53, 117, 133, 137), and 2) the feasibility of using cryopreserved material (133, 151).
Our interest in CLL derives primarily from the exploitation of human diseases as strategic models for defining
the in vivo biological role of CD38. The underlying working hypothesis is that CD38 is not a mere marker, but that
its surface expression has pathogenetic potential. In line
with this hypothesis, we have shown that CD38 ligation by
means of agonistic monoclonal antibodies is followed by
proliferation and blast transformation of a subset of CLL
cells, demonstrating that the molecule may perform as an
active signaling receptor (62). The in vitro signaling properties mediated by CD38 are significantly enhanced by the
simultaneous presence of IL-2, which acts through strong
upregulation of CD38 expression. To determine which
mechanism(s) maintain CD38⫹ cell proliferation, we showed
that CD38-mediated signals may be activated upon interaction with the cell surface CD31 ligand. CD38⫹ CLL cells
juxtaposed to murine fibroblasts transfected with CD31
exhibit increased growth and survival. Furthermore,
CD38/CD31 contacts upregulate the survival receptor
CD100, a semaphorin family member involved in sustaining CLL growth and survival (71). The model is indirectly
confirmed by evidence that nurselike cells (NLC) derived
from CLL patients express high levels of functional CD31
and plexin-B1, the high-affinity ligand for CD100 (71)
(Fig. 9).
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specificity of these models. CD38 has also been used for
gene therapy approaches relying on the selective killing of
tumor cells by means of oncolytic viruses.
A. CD38 as a Constitutive Target
CD38 is expressed at high epitope density by a variety of lymphoid tumors, including most cases of myeloma
(225), some cases of AIDS-associated lymphoma (144),
and many cases of posttransplant lymphoproliferations
(109). The marked quantitative differences in cell surface
expression between normal cells and their leukemic
counterparts made CD38 an attractive target for immunotherapy treatment.
In 1991, the G. T. Stevenson group (Tenovus, Southampton, UK) prepared a chimeric antibody (mouse Fab ⫻ human Fc) specific for human CD38. The recombinant
monoclonal antibody efficiently mediated antibody-dependent cellular cytotoxicity (ADCC) against a CD38⫹
lymphoid cell line when using human blood mononuclear
cells as effectors (319). The effector functions of T and
NK cells (both CD38⫹) proved not to be impaired or
influenced in any apparent way. More importantly, the
growth potential of erythroid and myeloid progenitors
was not inhibited, furnishing possible evidence that the
earliest stem cells do not express CD38 (86).
Along with attempts at using monoclonal antibodies
to redirect effector cells towards tumors, scientists exPhysiol Rev • VOL
plored another strategy in which monoclonal antibodies
are used as carriers of toxins. Myeloma had been identified early on as an appealing target for therapeutic applications. Anti-CD38 antibodies were devised to be used
alone or for enriching a therapeutic armamentarium
which was quite poor at that time. In 1994, V. Goldmacher
(ImmunoGen, Cambridge, MA) and K. C. Anderson (Harvard Medical School, Boston, MA) (124) developed a potent immunotoxin capable of killing human myeloma and
lymphoma cells, but with only limited toxicity to normal
BM progenitors. Another significant finding was that normal resting peripheral blood lymphocytes were not activated by the presence of the immunotoxin.
In spite of their promising results, these early investigations did not lead to clinical applications. The molecule’s widespread distribution in lymphoid, myeloid, and
epithelial cells as well as in specialized tissues and organs
including the eyes caused general reluctance to use CD38
as a target in human therapy (see Table 1).
A. Bolognesi et al. (Bologna, Italy) persisted in this
line of research and recently developed an immunotoxin
based on an anti-CD38 monoclonal antibody (IB4) coupled to saporin-S6, a type 1 ribosome-inactivating protein.
This drug was designed for ex vivo or loco-regional therapeutic applications in human myelomas and lymphomas
(27). The ability of this immunotoxin to eliminate cells
expressing the target was studied in vitro on selected
CD38⫹ human cells and cell lines. Concentrations as low
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9. CD38 as a pathogenetic agent in CLL. Left: CD38⫹ CLL lymphocytes (white arrows) interact with nurselike cells. Red staining: Alexa-red
phalloidin. Green staining: anti-CD31 followed by FITC-conjugated goat anti-mouse IgG. Images were acquired using an Olympus 1X71 confocal
microscope at ⫻60 magnification. Full experimental details may be found in Ref. 71. Right: schematic representation of the molecular interactions
taking place between CLL lymphocytes and closed microenvironments. The biological and clinical implications of these signals are listed in the
bottom part of the image.
FIG.
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
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S. Holmes (Domantis, Cambridge, UK) designed a
strategy of bypassing the intrinsic limitations of conventional monospecific murine monoclonal antibodies by exploiting antibody derivatives with dual specificity. The
monomeric domain antibodies (dAbs) were isolated using
phage display techniques by selecting independent specificities for CD38 and CD138, which are simultaneously
expressed by myeloma cells. When combined, the two
phage display ligands yielded a final product (dAbs) dual
targeting with good avidity human myeloma cells (CD38⫹/
CD138⫹). Cells expressing just one of the target molecules were only weakly stained or bound. The dual targeting derivative construct was also easily internalized,
highlighting its potential for use as an immunotoxin (320).
B. De Novo Induced Expression of CD38 for
Tumor Targeting
A growing body of data suggest that a positive therapeutic index may be generated for drugs or drug combinations by immunotherapeutic targeting of chemotherapyinduced antigens (296). The K. Mehta group (M. D. Anderson Cancer Center, Houston, TX) observed that the
expression of CD38 is highly sensitive to exogenous and
endogenous all-trans retinoic acid (ATRA) and derivatives and that the sensitivity is highly magnified in tumor
and leukemic cells (82).
These initial observations were reevaluated from
therapeutic perspectives in acute promyelocytic leukemia
(APL), as well as in other myeloid leukemias. ATRA is an
in vitro inducer at nanomolar concentrations of cell surface CD38 in myeloid leukemia blasts. The same reagent
is a key component in clinical differentiation therapy
adopted for APL cells, which are generally CD38⫺ before
treatment.
The CD38 molecules expressed de novo at high
epitope density may be used as therapeutic targets. Indeed, the combination of ATRA and an anti-CD38-gelonin
immunotoxin induces synergistic killing of leukemia cell
clones and blasts from patients (240).
Despite the good results of ATRA treatment, the drug
unfortunately has clinically significant side effects in
⬃20% of patients. The most important is the Retinoic Acid
Syndrome (RAS), a potentially fatal condition in APL
patients, marked by acute respiratory distress and pulmonary edema. Autopsies of RAS patients demonstrated extensive infiltration of ATRA-differentiated myeloid cells
into lungs, skin, kidney, liver, and lymph nodes. The only
available treatment consists of high-dose dexamethasone,
even though the mechanisms of action of the drug are still
unknown.
From this, we may speculate that RAS is secondary
to the aberrant interactions taking place between differentiated myeloid cells and host tissues. This may be at-
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as 100 pM of the immunotoxin completely inhibited protein synthesis. CD38⫹ neoplastic cells from non-Hodgkin
lymphoma patients were totally eliminated after treatment with the immunotoxin at a concentration of 10 nM.
Once again, CFU-c in culture from BM was maintained
after exposure to the immunotoxin. These results indicate
that IB4/saporin-S6 has strong and specific cytotoxic effects on selected CD38⫹ tumor cell lineages. On the basis
of these results, it is reasonable to propose clinical use of
IB4/saporin-S6 for ex vivo purging of undesired cells (e.g.,
for the depletion of contaminating neoplastic cells in
aphereses obtained from G-CSF-treated patients) or for
loco-regional therapies of CD38⫹ tumors (27). The likelihood of developing clinical applications using the immunotoxins grew even stronger after their behavior was
more systematically analyzed in vivo (see summary in
Ref. 199).
Further impetus for designing clinical models based
on anti-CD38 reagents came from significant structural
modifications of the antibodies and variations in the species used. P. Parren (Genmab, Utrecht, The Netherlands)
prepared a vast panel of human anti-CD38 monoclonal
antibodies raised after immunizing mice transgenic for
human Ig genes. These monoclonal antibodies stained
both CD38⫹ cell lines and freshly isolated myeloma cells.
The reagents revealed potent ADCCs against CD38⫹ cell
lines of B derivation, against clinical samples of myeloma
and plasma cell leukemias (both CD38⫹/CD138⫹). The
antibodies also elicited a significant complement-dependent cytotoxicity (CDC) against primary myeloma cell
cultures isolated from a panel of 13 patients (320).
The growth of a human B lymphoma xenografted in
SCID mice was strongly inhibited in both preventive and
therapeutic settings. Similar effects were observed using
plasma cells from human rheumatoid synovium engrafted
in SCID mice. Of particular relevance for biochemists, the
human monoclonal antibody from Genmab had the
unique ability to inhibit the enzymatic properties exerted
by cell surface CD38, a result never achieved with mouse,
rat, or rabbit antibodies (320).
A team from MorphoSys (Martinsried, Germany) produced a number of fully-human antibodies selected by
cell-panning strategies from a unique phage-display library (332). The affinity constants of the antibodies were
in the low nanomolar range, and they efficiently stained
myeloma cells by flow cytometry. In addition to the ability
to kill CD38⫹ cell lines and clinical samples in ADCC
tests, the antibodies did not exert negative effects on
circulating leukocytes or BM progenitors. Indeed, the effects related to the exposure of anti-CD38 monoclonal
antibodies in normal blood progenitors were negligible,
and clonogenic potential appeared to be unaffected. The
therapeutically favorable characteristics displayed in
vitro were confirmed by the reduction of tumor growth in
a SCID mouse xenograft model (320).
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C. CD38 as a Target for Gene Therapy
CD38 was also used for gene therapy applications
using modified viruses. To guarantee therapeutic success,
transfer vehicles for gene therapy must be capable of
transducing target cells while avoiding bystander cells. In
several instances, there is an imbalance between transduction efficiency of viral vectors and cell tropism not
compatible with in vivo use. The lack of appropriate
targeting has limited the potential of gene therapy for
many years (reviewed in Ref. 344).
The strategy adopted by the S. J. Russell group (Mayo
Clinic, Rochester, MN) was to use oncolytic viruses as
anticancer drugs. These viruses propagate selectively in
tumor tissue and destroy it without causing excessive
damage to normal or surrounding noncancerous tissues.
The group at Mayo Clinic provided an in vivo demonstration of antibody-directed tumor destruction by ad hoc
retargeting of oncolytic viruses. They observed that live
attenuated measles viruses of the Edmonston lineage
have potent anti-tumor activity; however, they are not
entirely tumor specific because of the wide distribution of
their native receptors, namely, CD46 and SLAM. This
limitation was overcome by retargeting the viruses by
inserting single-chain antibody surface fragments; this
consents full rescue and propagation of the virus and, at
Physiol Rev • VOL
the same time, provides a receptor for specifically infecting the tumor cells. Viruses retargeted to tumor-selective
CD38 and other surface molecules efficiently entered neoplastic cells through their respective targeted pseudoreceptors either in vitro or in vivo, but not through CD46 or
SLAM. When administered intratumorally or intravenously to mice bearing human tumor xenografts expressing CD38, the targeted viruses demonstrated specific receptor-mediated anti-tumor activities (257).
Antiviral immunity remains a significant barrier to
the clinical efficacy of oncolytic viruses. Nonetheless, it is
reasonable to expect that this limit will eventually be
overcome by new strategies for evading the immune system and the use of immunosuppressive drugs (157).
X. CONCLUDING REMARKS
The questions surrounding CD38 and CD157, and
ectoenzymes in general, are fascinating and continue to
prompt experiments and kindle debate. A review published more than 10 years ago by our group (227) ended
with no firm conclusions as to how the two molecules
actually function in vivo. Today, the situation has changed
significantly: we can now start to piece together a general
picture from the mosaic of information emerging from a
number of different perspectives, with the ultimate aim of
integrating these insights into a single, coherent view.
The first solid data are that CD38 is old and phylogenetically conserved. The human variant continues to
share ⬃35% identity with that of a primitive sea mollusk.
Of even greater note, the enzymatic activity of the molecule has been maintained intact over the entire known
course of its evolution. The salient difference between
mammalian CD38 and Aplysia cyclase lies in the acquisition by the former of an additional location on the cell
surface. From a teleological perspective, this change may
reflect increased biological complexity and the corresponding need for new functions in different locations. It
would also seem to imply new role(s) for the reaction
products outside of cells. Yet, whereas cADPR, ADPR,
and NAADP play an essential and nonredundant role as
Ca2⫹ mobilizing agents inside the cell (209), no clear
physiological function has been identified for them in the
extracellular fluids. Several models have been proposed
as to how the extracellularly generated products may
reach their final destination inside the cell, even though
they appear quite complex (60).
Another way to look at the picture gives privilege to
the substrate of the enzymatic activity. CD38 is the most
important NADase in mammals, where it degrades NAD⫹,
which is released in significant amounts during tissue
inflammation and consequent cell death. The coordinated
enzymatic activities of CD38 and CD157 and of a number
of nucleotide-metabolizing enzymes would therefore per-
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tributed to the effects elicited by ATRA on the mechanism(s) regulating adhesion between myeloid cells and
endothelium in the lungs. Indeed, ATRA treatment was
shown to modulate the secretion of certain cytokines as
well as the expression of different adhesion molecules,
among which is CD38 (68, 108).
These effects are mediated by the retinoic acid receptor-␣ (RAR-␣), which acts as a ligand-inducible transcription factor, while the RA response element is localized in the first intron of the CD38 gene (82, 92).
Intense cross-talk between the CD38 expressed by
myeloid cells and the CD31 present on the surface of
endothelial cells lining lung small vessels is likely to occur
and to activate signal transduction pathways in both cell
partners. This event could be the first step towards the
cytokine storm which characterizes the late phases of the
disease. Although it has not been described in individuals
taking retinoids for other reasons, RAS cannot be attributed to retinoids alone; indeed, inorganic arsenic trioxide
(As2O3 or ATO), which was recently proposed as an alternative treatment for APL patients, provokes the same
syndrome in some instances. Preliminary data indicate
that ATO is also a potent inducer of CD38 expression and
that this compound may alter the tendency of myeloid
cells to adhere to the vessel walls (S. Deaglio, unpublished observations). This may indicate that CD38 is a link
between RAS induced by ATRA or by ATO.
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
An alternative possibility is that the localization on
the cell surface serves to inactivate CD38 and store it
outside its true working environment in the cytosol. According to this view, the enzymatic functions would be
superfluous when the molecule is expressed on the cell
membrane, where its substrates are largely unavailable.
They would become prominent, instead, when the molecule is expressed in the cytoplasmic or nuclear compartments of the cells (65).
Each of the models outlined has some merit, but they
all fall short of providing a single and cohesive account of
how and where the receptorial functions of CD38 integrate with its enzymatic activities.
It is the view of this Lab that the CD38 gene family
represents a bridge between innate and adaptive immunity. According to this hypothesis, the enzymatic activi-
FIG. 10. Proposed model that integrates enzymatic and receptorial functions
mediated by CD38. Details are outlined
and discussed in section X.
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mit recovery of energetically costly products, which
would otherwise go wasted. Indeed, CD38 and CD157 are
part of a larger family of nucleotide-metabolizing (ecto)enzymes sharing a common evolutionary history. The network includes CD26, CD39, CD73, and PC-1, along with
P2X7 (formally not an ectoenzyme) and the related ADP
ribosyl-transferases/ARTs. These molecules tend to cluster in specialized areas of the plasma membrane, creating
a sort of hub for external activities, which may yield
products eventually destined for internal cell use (Fig. 5).
However, new roles as signaling molecules regulating life
and death are emerging for each of these substrates,
intermediates, final products and for the enzymes in
charge of their metabolism (193). It is thus safe to conjecture that this network serves more important purposes
than mere scavenging.
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CD38 signals in human peripheral blood leukocytes are
followed by release of significant amounts of defensins
(A. Funaro, E. Tibaldi, F. Saccucci and F. Malavasi, unpublished data). This may indicate that when CD38 acquired its surface expression, it connected with the most
efficient defense/offense system of the cell. We are also
collecting preliminary evidence along these lines from the
association between CD38/CD157 and toll-like receptors.
Further substantiation for our view derives from the
structural/functional relationship between CD38 and
members of the Ig superfamily, first with the receptor for
the Ig Fc region (FcR) and later with antigen receptors.
FcRs are expressed by different cell types, the most relevant of which for our present purposes are NK cells. NK
cells are the most important lineage controlling the elimination of tumor cells and exogenous pathogens and operate through an age-old system of recognition (56). In NK
cells, CD38 developed a symbiosis with CD16, the lowaffinity receptor for IgG. Later on in its evolution, CD38
contacts widened by acquiring lateral associations with
TCR and BCR complexes. Support of the relevance of this
type of cross-talk comes from recent findings that CD38
plays a prominent role in the formation of the immune
synapse, the most sophisticated and well-developed sys-
FIG. 11. Proposed model of evolution
of the CD38 gene family. The working hypothesis is that the CD38 gene family acts
as a bridge connecting innate (blue) and
adaptive (pink) immune systems. Mya, million years. NLR, nucleotide binding domain, leucine-rich repeat containing family; TLR, Toll-like receptors; RLH, retinoic
acid inducible gene-I like RNA helicases.
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ties would modulate crucial immune functions such as
migration, defense from pathogens, cell activation, and
immune synapse formation. At the same time, the enzymatic functions are regulated through lateral and frontal
associations with surface molecules sharing an Ig-like
domain (Fig. 10). Although still partially speculative, the
hypothesis is supported by evidence from different fields.
To begin with, CD38 plays an important role in chemotaxis, which is crucial for both innate and adaptive
immune responses. In fact, the most striking feature of
the CD38 KO mouse is its inability to direct neutrophils to
sites of infections, a typical context of innate immunity
(271, 272). Moreover, data from human myeloid cells and
human lymphocytes suggest that CD38 can also influence
their migration into the lymph nodes where the antigen is
taken up, processed, and presented, a typical context of
adaptive immunity (98).
A second line of evidence derives from the link between CD38/CD157 signaling pathways and the release of
defensins, which are among the most ancient and basic
forms of defense against pathogens. Dating back as far as
plants, defensins were later acquired by polymorphonucleates as a means of rapidly eliminating harmful external and internal agents (178). We have observed that
THE ADP RIBOSYL CYCLASE/CD38 GENE FAMILY
Physiol Rev • VOL
cADPR from NAD⫹ in the brain, where NAD⫹ is as abundant as ATP is in neuronal cells (172).
The data and models presented and discussed in this
review undoubtedly reflect our background, resulting in a
strong immunological orientation. It is important to recognize, however, that immunity is a relative newcomer in
the history of life, and the scientific community may have
missed more informative clues to be found in older systems. Future research over the next few years should
seek to fill this gap.
ACKNOWLEDGMENTS
Thanks are given to H. C. Lee (Minneapolis, MN and Hong
Kong, China) and to Q. Hao (Ithaca, NY) for kindly providing
figures about enzymatic activities and crystal structures, respectively. G. Magni (Ancona, Italy) contributed to the design of the
ectoenzyme network figure. Thanks are also given to F. Lund
(Saranac Lake, NY) for friendly assistance.
Dr. L. McLean provided a passionate and inspired assistance in the stylistic assembly of the review.
Address for reprint requests and other correspondence: F.
Malavasi, Laboratory of Immunogenetics, Dept. of Genetics,
Biology, and Biochemistry, via Santena 19, 10126 Torino, Italy
(e-mail: [email protected]).
GRANTS
This work was supported by grants from University of
Torino (F. Malavasi, S. Deaglio, A. Funaro), Associazione Italiana Ricerca Cancro (AIRC; Milan, Italy) (F. Malavasi, S. Deaglio), Progetti di Ricerca di Interesse Nazionale (PRIN; Rome,
Italy) (F. Malavasi, S. Deaglio, A. Funaro), Ricerca Sanitaria
Finalizzata (Regione Piemonte, Turin, Italy) (A. Funaro), and the
Chronic Lymphocytic Leukemia Global Research Foundation
(CLL-GRF) (S. Deaglio) and Telethon (A. L. Horenstein).
Fondazione Internazionale Ricerca in Medicina Sperimentale (FIRMS), Compagnia di SanPaolo, Fondazione CRT, and
Fondazione Cariverona provided valuable financial contributions.
T. Vaisitti is supported by a FIRC fellowship (Milan, Italy).
S. Aydin is supported by Dr. Werner Jackstaedt-Stiftung (Wuppertal, Germany).
S. Aydin is on a leave of absence from the Department of
Hematology, University of Essen Medical School, Essen, Germany and is a member of the PhD Program “Tumor Localization,” University of Torino.
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