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10.1146/annurev.immunol.22.012703.104543
Annu. Rev. Immunol. 2004. 22:891–928
doi: 10.1146/annurev.immunol.22.012703.104543
c 2004 by Annual Reviews. All rights reserved
Copyright °
First published online as a Review in Advance on December 16, 2003
CHEMOKINES IN INNATE AND ADAPTIVE HOST
DEFENSE: Basic Chemokinese Grammar
for Immune Cells
Antal Rot1 and Ulrich H. von Andrian2
1
Novartis Institute for Biomedical Research, Vienna, A-1235 Austria;
email: [email protected]
2
CBR Institute for Biomedical Research and Department of Pathology, Harvard Medical
School, Boston, Massachusetts 02115; email: [email protected]
Key Words chemokine receptors, chemotaxis, endothelial cells, lymphocyte
trafficking
■ Abstract Chemokines compose a sophisticated communication system used by
all our cell types, including immune cells. Chemokine messages are decoded by specific
receptors that initiate signal transduction events leading to a multitude of cellular
responses, leukocyte chemotaxis and adhesion in particular. Critical determinants of
the in vivo activities of chemokines in the immune system include their presentation
by endothelial cells and extracellular matrix molecules, as well as their cellular uptake
via “silent” chemokine receptors (interceptors) leading either to their transcytosis or
to degradation. These regulatory mechanisms of chemokine histotopography, as well
as the promiscuous and overlapping receptor specificities of inflammation-induced
chemokines, shape innate responses to infections and tissue damage. Conversely, the
specific patterns of homeostatic chemokines, where each chemokine is perceived by
a single receptor, are charting lymphocyte navigation routes for immune surveillance.
This review presents our current understanding of the mechanisms that regulate the
cellular perception and pathophysiologic meaning of chemokines.
INTRODUCTION
The immune system consists of billions of motile cells that roam at large in the
body. In need of communication signals to navigate these cells along their convoluted pathways in time and space, to orchestrate their interactions and enable
them to form architecturally complex organs of their own, the immune system
turned to chemokines. Chemokines are building blocks of the most versatile, coherently functioning system of intercellular communication signals. Chemokine
messages are decoded through specific cell-surface receptors. Upon chemokine
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binding, these receptors unleash cascades of intracellular secondary mediators
that turn on cell-specific intrinsic functional programs, including directional migration, the best-known effect of chemokines. The sum of individual “cell reflexes”
results in complex system responses during both steady-state conditions and innate and adaptive immune reactions. Like any other communication system, the
chemokine network bears several noteworthy attributes of a language, which we
call here “Chemokinese.” Like human languages, which follow general rules of
grammar, Chemokinese also has rules. In this review, we describe the basic grammar of Chemokinese and how it applies to cell communication in the process of
inflammation and immune responses.
CHEMOKINESE ALPHABET
Chemokines are defined independently of their function, based on their amino acid
composition, specifically on the presence of a conserved tetra-cysteine motif (1–3).
The relative position of the first two consensus cysteines (either separated by a
non-conserved amino acid or next to each other) provides the basis for division of
chemokines into the two major subclasses, CXC and CC chemokines, respectively
(Figure 1). Three homologous molecules are also regarded as chemokines. These
are CX3CL1, with three intervening amino acids between the first cysteines, and
XCL1 and XCL2, which lack two out of four canonical cysteines. To date, the official nomenclature accounts for 43 human chemokines (4, 5) (Figure 1). However,
isoforms and polymorphisms, splice variants and enzymatically processed forms,
as well as chemokines encoded in viral genomes enlarge substantially the number
of distinct chemokine molecules that can naturally affect human cells. Additional
rare chemokines may be stashed away in the human genome waiting to be discovered. But even at their presently known diversity, chemokines, through almost
infinite combinatorial possibilities of their simultaneous or sequential appearance,
can convey the most complex cellular messages.
Chemokines carry encrypted messages to cells that have the means to decode
them, and hence are operating as a communication medium, a cell language. Individual chemokines may be compared to distinct ideograms, symbols representing a
particular idea, word, or morpheme as, for example, those in Sumerian cuneiform
scripts, Egyptian hieroglyphs, or some characters in Chinese and Japanese languages. Chemokinese dispatches are prompted by diverse stimuli from many
different cell types. Perceived and decoded, these messages can influence the
most profound aspects of a cell’s life, including not only eponymous chemotaxis
and adhesion but also proliferation, maturation, differentiation, apoptosis, malignant transformation, and dissemination (6). Chemokines on the whole can affect
any cell type. However, notable specificity patterns of responsiveness to different
chemokines have been identified, determined by the expression of the apposite
chemokine receptors.
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HOW CELLS GRASP CHEMOKINESE
The Chemokine Receptors
The recognition of chemokine-encoded messages is mediated by specific cellsurface G-protein-coupled receptors (GPCRs) with seven transmembrane domains.
The human chemokine receptor system at present consists of 19 different GPCRs
(7) (Figure 1). The GPCR family is the most diverse class of cell-surface receptors. Specific GPCRs perceive signals from ligands as varied as hormones; biogenic
amines; neuropeptides; neurotransmitters; classical chemoattractants; lipid mediators; pheromones; sweet, bitter, and umami tasting molecules; odorants; and light
photons.
Chemokine GPCRs carry out three fundamental parts of the chemokine-induced
“cellular reflex”: message acquisition, semantic extraction (decoding), and initiation of cell responses. These three functions are not interdependent. In this
respect, Chemokinese is similar to human languages where word perception, interpretation of meaning, and induction of a response (or lack thereof) can also
be separated. The message acquisition, i.e., chemokine binding to a particular receptor, is determined by receptor affinity, which varies greatly between ligands
and does not necessarily translate into functional potency (8, 9). The meaning
of a chemokine is influenced by its position on the agonist-antagonist scale for
a particular receptor. The ability either to shift the receptor into its “productive”
signaling conformation or to prevent such a shift determines a chemokine’s agonist and antagonist potency, respectively (10, 11). In addition, a chemokine’s
meaning depends on the magnitude of the elicited response (efficacy) and ability
to induce various regulatory and signal transduction pathways, which determine
the actual response. The efficacy and the quality of the response also depend on
the chemokine-induced shift in receptor configuration, which, however, may be at
variance with that determining chemokine potency (10). For the same receptor the
elicited functions may differ, depending on the ligand (11) as well as the microenvironment, including available G-protein isotypes, signal regulatory pathways,
etc.
It will take some time before the molecular interactions responsible for matching
43 chemokines and 19 receptors will become clear because these interactions are
likely to vary for each receptor and ligand. Also, the determinants of agonism
and antagonism are different for each chemokine and its receptor(s). The multiple
signaling pathways (12) and cell responses induced by chemokines vary, too, as
they depend on the responding cells and a multitude of other factors. However,
there is one response, chemotaxis, that is elicited by (almost) all chemokines in
(almost) all receptor-bearing cells. Experimental work of the past few years and
analogies with the mode of action of other GPCRs, especially those for classical
chemoattractants, have identified many of the molecular events that may lead from
chemokine GPCRs to cell locomotion.
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From GPCR to Chemotaxis
Leukocytes stimulated by chemoattractants assume a polarized morphology (13).
They become elongated and develop a wide lammellipod (pseudopod) at the leading edge and a tail-like projection at the trailing end (uropod). The generation
of filamentous actin at the pseudopod leads to its extension, which together with
uropod retraction drives cell locomotion (13, 14). However, polar leukocyte morphology is not a response to a chemotactic gradient, as it can be observed during
spontaneous random walk and chemokinesis, agonist-stimulated migration that
lacks directionality (15). Chemotaxis combines enhanced-rate locomotion with a
gradient-imposed, unidirectional character of response. When the gradient is reversed during chemotaxis, leukocytes either retract the pseudopod and form a new
one at the tail end (16) or, more often, make a U-turn while maintaining their original pseudopod (15, 17). This suggests that in moving leukocytes the pseudopod is
specialized for gradient perception. The relative increase in concentration of some
chemokine receptors at the leading edge of moving leukocytes (18) may be the
first step in the generation of intracellular mediator cascades at the pseudopod.
Chemokine receptors function as allosteric molecular relays where chemokine
binding to the extracellular portions modifies the tertiary structure of the receptor, allowing the intracellular part to bind and activate heterotrimeric G-proteins.
In response, the activated G-proteins exchange guanosine diphosphate for guanosine triphosphate (GTP) and dissociate into α- and βγ -subunits. Chemokine receptors can couple to several different Gα isotypes (19, 20). The βγ -subunits
that dissociate from the pertussis toxin-sensitive Giα mediate chemokine-induced
signals (21, 22) by activating the phosphoinositide-3 kinases (PI3K) (Figure 2),
which lead to generation of phosphotidylinositol-3,4,5-trisphosphate (PIP3). The
importance of this reaction is evidenced by the deficient migration of myeloid
leukocytes to chemokines in mice lacking PI3Kγ (23). Lymphocyte chemotaxis is
not severely compromised in PI3Kγ -deficient mice (23). This implies that either
different signal transduction mechanisms prevail in chemokine-induced lymphocyte migration or other PI3K isotypes, recently suggested to amplify PI3Kγ mediated reactions, could play a more important role in lymphocytes than in
myeloid cells (24, 25). PI3K and its product PIP3 translocate to the pseudopod
where they colocalize with the small GTPase Rac (26, 27). PIP3 activates Rac
through specific guanine nucleotide exchange factors (GEFs) (28, 29). In addition, PIP3 serves as a docking site for protein kinase B, which also translocates
to the pseudopod and can induce actin polymerization (30). Rac is indispensable for leukocyte migration (31). Its downstream effectors include p21-activated
kinase (PAK) and the Wiskott-Aldrich Syndrome protein (WASp) homologue,
WAVE, which stimulate actin-related protein (Arp) 2/3. This induces focal actin
polymerization, responsible for the development and forward extension of the
pseudopod.
When exogenous PIP3 is introduced into a cell, it induces endogenous PIP3,
suggesting a self-amplification loop that establishes intracellular gradients of
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effectors in the pseudopod (32). This also implies that the PIP3-induced activation of Rac can signal back to one of the PI3K family members, possibly PI3Kδ
(24).
The events that lead from GPCR signal to Rac-initiated actin polymerization
explain how cells that read Chemokinese gradients can migrate in response. However, reading and understanding are not the same. The signals centering on Rac
are sufficient to activate the actin-based engine that propels the cells, but they
do not contribute to the “comprehension” of a gradient’s direction and, therefore,
cannot support the unidirectional bias of locomotion, the hallmark of chemotaxis.
The latter requires another Rho GTPase, Cdc42. Without Cdc42, leukocytes exhibit a random walk, rather than directed migration, when placed in a chemotactic
gradient (33–37). Curiously, the target of Cdc42, PAK1, acts upstream of it. Activated directly by Gβγ , PAK1 binds Pixα, a GEF that is specific for Cdc42, to form a
complex that recruits and activates Cdc42 (38). This signaling complex is responsible for F-actin nucleation via activated Arp 2/3 and exclusion of PI3-phosphatases,
the negative regulators of PIP3, from the leading edge of the cell (38, 39). Gradient
sensing is also dependent on functional PI3K, although it is not entirely clear how
(38). The mechanism that couples Cdc42-mediated cell orientation and steering
to the Rac-driven actin motor has not been determined. Additionally, the events
that lead to Cdc42- and Rac-mediated actin polymerization (Figure 2) explain only
what happens in the pseudopod, i.e., the front part of cells, following the beckoning
of chemokines.
Dual Signaling Pathways in Moving Leukocytes
Formyl peptide induces the activation of different sets of mediators at the pseudopod and the uropod of moving neutrophils (40). In parallel to the sequence leading
to Rac activation at the pseudopod, another pathway leads through pertussis toxin
insensitive Gα 12/13 to the activation of Rho by Rho GEFs at the uropod (40). Activated Rho, through its effector p160ROCK, a serine/threonine kinase, induces focal activation of myosin II, formation and contraction of actin-myosin complexes,
thereby leading to retraction of the uropod (41, 42). In addition, Rho prevents the
formation of lamellipodia at the trailing end (43). These two alternative signaling
pathways involving either Rac or Rho are mutually inhibitory, which explains why
they are spatially confined to the pseudopod and uropod, respectively. Together
they induce and maintain functional and morphological cell polarity and drive locomotion (40). The equilibrium between GPCR signaling pathways through Gi and
Gα12/13 may also control the balance between cellular movement toward or away
from the source of a gradient. For example, sphingosine-1-phosphate (S1P) can
induce either chemoattraction or repulsion depending on the receptor it is using.
S1P3 (Edg3) is an “attractant” receptor, which upon stimulation with S1P gives rise
to both Gi/Rac and Gα12/13/Rho activation pathways. It can be converted to a “repellant” receptor by simply blocking the Gi/Rac pathway with pertussis toxin (44).
Determining whether these findings also apply to chemokine-driven leukocyte
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migration is important. Leukocytes do not bear S1P3, and whether chemokinetriggered GPCRs are coupled to the Rho-activating G12/13 or Gq/11 pathways is
still unknown (45). Nevertheless, it is attractive to speculate that similar mechanisms may influence chemokine-induced leukocyte migration, at least in some
settings. For example, CXCL12 and CCL26 can induce chemorepulsion through
CXCR4 and CCR2, respectively (46, 47). Chemokine-driven migration away from
the source of a chemokine may promote leukocyte departure from tissues, as was
suggested for CXCL12-mediated expulsion of newly generated T cells from the
thymus (48) and prevention of T-cell entry into bone marrow (46). By analogy
with the paradigm observed for S1P3, it is possible that the ability of CXCL12 to
induce either chemoattraction or chemorepulsion of T cells is determined by the
balance between alternative signal transduction pathways.
The intracellular events described here, which lead from GPCRs through PI3K
to small GTPases, appear to be necessary and sufficient to mediate chemokineinduced leukocyte chemotaxis at least in some leukocyte types. By contrast, the
chemokine-induced intracellular signals leading to rapid integrin activation, which
enables firm leukocyte–endothelial cell (EC) adhesion, are not yet fully characterized. Potential effectors include Rho (49) and the small GTPase Rap1 (50–52).
In addition, chemokine GPCRs activate many other mediators and pathways that
induce other cell responses including exocytosis, proliferation, gene transcription,
and apoptosis. Inevitably, these mediators, through known or still-to-be-discovered
pathways and feedbacks of tightly woven intracellular signaling networks, may
also influence cell migration. The apparent ability of chemokine receptors to
dimerize and heterodimerize introduces a further dimension of complexity into
chemokine-induced signaling (53, 54). For more details on chemokine signaling,
we refer the reader to recent reviews on this subject (36, 55–57).
Shutting Off the GPCR Signal
Chemokine receptor signaling is transient because the mechanism of activation
contains a built-in shut-off sequence. The Gα subunits have intrinsic GTPase activity to hydrolyze GTP and reunite with Gβγ to return to the initial conformation of
inactive heterotrimers. Molecules called regulators of G-protein signaling (RGS)
can modify the GTPase activity of the Gα subunits (58, 59). RGS act bimodally, enhancing the GTPase activity of some Gα isotypes while inhibiting it in others (60),
and show specificity for individual chemokine receptors (61, 62). Two additional
mechanisms of chemokine receptor silencing include (a) desensitization, caused
by steric hindrance of G-protein activation due to receptor phosphorylation by
G-protein-coupled receptor kinases (GRK), and (b) downregulation caused by βarrestin- or adaptin-2-mediated receptor sequestration and internalization through
clathrin-coated pits or caveolae (63–65). Desensitization and internalization are
regulated separately and require the phosphorylation of different serine residues
in the C-terminal tail of chemokine receptors (66). Internalization, apparently, can
even be uncoupled from signaling through Gαi (67). However, as suggested by
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the lack of CXCL12-induced lymphocyte chemotaxis in β2-arrestin and GRK6deficient mice, these molecules may also play yet unknown positive regulatory
roles in chemokine signaling (68). The pathways leading to either degradation or
recycling of chemokine receptors following their internalization are determined
by the guardians of all vesicular machinations, Rab GTPases (69), which also
influence the surface reexpression of internalized chemokine receptors (67, 70).
Alternative Signaling Mechanisms
Intriguingly, the cell nucleus may be an additional site for chemokine signaling.
Specific nuclear localization leading to changes in morphological and functional
cell parameters has been observed with the natural nonsecreted variant of CCL27
called PESKY (71). The secreted CCL27, as well as other chemokines, may be
targeted to the nucleus, following internalization through their GPCRs (71, 72). It
is not clear what the molecular nature of putative nuclear chemokine receptors is
and too early to judge how important their function may be.
Sulfated sugars of the glycosaminoglycan (GAG) family, such as heparan sulfate
and chondroitin sulfate, bind chemokines and in response can mediate outside-in
signaling through the proteins they are decorating. For example, CCL5 signals
in HeLa-CD4 cells that express GAGs and are completely devoid of GPCRs, but
does not signal in mutant cells that lack GAGs (73). This GPCR-independent
signal is mediated by GAG-decorated CD44 (74). CXCL4, in addition to using
CXCR3B (75), may also signal through chondroitin sulfate–decorated membrane
molecules on neutrophils, monocytes, and lymphocytes (76). GAGs on a target cell
membrane may also influence chemokine signals by another mechanism. GAGbound chemokines, owing either to their presentation to GPCRs in cis-geometry
or to GAG binding-induced changes in their secondary structure (77), may gain
enhanced agonistic properties (78, 79). However, the best known and arguably most
important role of GAGs is their presentation of chemokines in trans-geometry.
WRITTEN CHEMOKINESE
Notes on Sugar
To carry their message to remote target cells, chemokines have to diffuse away
from their source, hence remain soluble. However, in vivo chemokines interact with GAGs, which can limit their dissemination. GAGs decorate proteins in
the extracellular matrix and on cell surfaces and not only interfere with chemokine
diffusion, but also provide highly specific substrates onto which Chemokinese
messages are “written.” All chemokines bind GAGs, yet they show remarkable
disparity in affinities for various GAGs and vice versa (80, 81). This is owing,
in part, to the diverse functional domains that different chemokines use for GAG
binding (82). For example, CXCL8 uses its C-terminal α-helix to bind heparan
sulfate (83), CCL3—three noncontiguous basic amino acids at positions 18, 46,
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and 48 (84)—and CCL5—two amino acid clusters, 44–47 and 55–59 (85). This
means that chemokines not only encode distinctive meanings perceived through
their cognate receptors, but also contain within their structure clues as to where
the message should be posted.
Written Chemokinese is read by contact, like the Braille language of the blind,
whereby leukocytes adhere to surfaces onto which chemokines are immobilized.
Chemokines written on GAGs are not like words written in stone, impressed into
clay or printed on paper. Because of the changing equilibria of chemokine production, diffusion, GAG-immobilization, mobilization, and consumption, Chemokinese writing is similar to the way text changes during electronic word processing,
where words on the computer screens are written, rearranged, deleted, and written again. It has not been determined if GAG-bound chemokines can signal as
complexes through chemokine GPCRs or if chemokines must first dissociate from
GAGs to interact with their receptors. GAG-immobilized chemokines may be
deposited in domains directly accessible to leukocytes or in concealed microenvironments. Therefore, the regulation of in vivo activity of chemokines may take
place at the level of their GAG immobilization and mobilization. For example, the
digestion of GAG-bearing molecules by specific enzymes may either downregulate
chemokine activity as a result of chemokine removal from microanatomical sites
that are “visible” to leukocytes (86) or expose the previously concealed activity
by releasing chemokines from sequestered stores (87). Also, chemokine immobilization may be influenced by GAG synthesis and sulfation (88) and by soluble
GAGs (89, 90).
Complexing with GAGs may serve to neutralize chemokines stored in T-cell
granules (91). Other cell types can also store and release chemokines, demonstrating that the information storage function of written languages is also a feature of
Chemokinese. Intracellular chemokine depots serve as small souvenirs from the
past or crib notes for the future. For example, following an inflammatory insult,
ECs store some of the chemokines they produce in Weibel-Palade bodies (92). The
stored chemokines can be released instantaneously upon repeated inflammatory
stimulation. Neutrophils, eosinophils, cytotoxic T cells, and mast cells carry stored
chemokine in case they have to communicate in a hurry (91, 93, 94). Because they
store chemokines, including CXCL1, CXCL4, CXCL5, CXCL7, CXCL8, CCL1,
CCL5, and CCL7, platelets, handicapped by their inability to synthesize proteins
de novo, are by no means inarticulate (95, 96).
Chemokines not only can be immobilized by GAGs, but also can attach to
other natural and artificial substrates, including polycarbonate membranes used
in Boyden-type chambers or transwells. This allows chemokines to induce haptotaxis, directed migration to substrate gradients, the mechanism responsible for
in vitro leukocyte migration to CXCL8 and CCL5 (97, 98). In the context of
migration induced by immobilized chemokines, the term haptotaxis is used with
considerable corruption of the original denotation, which stands for movement
along gradients of adhesion molecules (99). With the exception of CX3CL1 and
CXCL16, chemokines are not adhesive per se, but they induce leukocyte adhesion
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by activating integrins (100), which allows chemokines to operate at the blood-EC
interface and induce leukocyte adhesion and emigration.
Writing Is on the (Vessel) Wall
Chemokine immobilization by GAGs on the luminal surface of ECs is a prerequisite for optimal progression of leukocyte-EC adhesion (101, 102) during both
chemokine-induced inflammatory recruitment and constitutive homing of leukocytes to tissues. The contribution of GAG binding to the in vivo proemigratory
activity of chemokines has been formally demonstrated first for CXCL8 (103)
and recently also for CCL2, CCL4, and CCL5 (104). Leukocytes adhere to the
endothelium stepwise, in a process that takes place in the following sequence only.
First, leukocytes establish a loose tethering interaction with ECs. If this interaction
persists, owing to the shear stress exerted by the bloodstream, it manifests as leukocyte rolling. Tethering and rolling are mediated by selectins and their ligands (105,
105a) as well as by integrins of the α 4 subfamily (106, 107). Rolling leukocytes
become activated by EC-bound chemokines that induce a rapid increase in the
affinity of α 4 and/or β 2 integrins (108–110). Next, adherent leukocytes spread and
transmigrate across the EC barrier in a process that, at least in vitro, can be induced
by apically immobilized chemokines and the presence of fluid shear stress (111–
113). Thus, a chemokine immobilized on the apical EC surface, but not soluble
chemokines, may accomplish (a) stimulation of leukocyte tethering and rolling,
(b) induction of firm adhesion, and (c) initiation of lymphocyte transmigration (111,
112). Other chemokines may act sequentially and divide the roles in induction of
firm adhesion and transmigration (114) or use two alternative receptors for these
two steps, as apparently happens with CCL5, which signals to monocytes through
CCR1 and CCR5 to induce adhesion and transmigration, respectively (115).
Irrespective of its exact function, the key aspect of GAG-mediated chemokine
presentation on the EC surface is to provide a mechanism of directing the chemokine
signal to leukocytes that have already initiated interactions with the EC and away
from freely circulating leukocytes. The latter, when stimulated by chemokines, lose
their ability to tether and emigrate (116, 117). Thus, an immobilized chemokine on
ECs induces leukocyte adhesion and emigration, whereas a blood-borne chemokine
functions as an adhesion inhibitor.
There are indications that specific mechanisms select tissue chemokines to
appear on the luminal EC surface. For example, of the two CCR4 ligands capable
of in vivo T-cell recruitment into the skin, CCL17, but not the more potent CCL22,
preferentially appears on the EC surface (118, 119).
Editor of Chemokinese Graffiti
Tissue-derived chemokines can cross the EC barrier passively through intercellular junctions. In addition, venular ECs can internalize and transport chemokines
in an abluminal-to-luminal direction (103). These two alternative routes are mutually nonexclusive. However, the pericellular route may bypass the EC membrane
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domains capable of efficient chemokine presentation (Figure 3). The chemokine
specificity fingerprint of in situ binding to venular ECs (120) suggests that Duffy
antigen, which is expressed by these cells (121), may contribute to chemokine
transport by ECs (103, 120). Duffy antigen (also known as Duffy antigen receptor for chemokines, or DARC), originally described on erythrocytes, is a serpentine seven-spanner that lacks a critical tripeptide DRY motif that is required
for GPCR function (122). Accordingly, Duffy antigen does not signal when it
binds one of its numerous ligands of the CC and CXC families. Duffy antigen
was recently grouped with D6, another nonsignaling seven-spanner that binds
multiple CC chemokines (123). Their suggested name, “interceptors,” [which
stands for chemokine internalizing (pseudo)receptors, abbreviated CIPR-1 and
CIPR-2, respectively], reflects their main function in nucleated cells (124).
As Duffy antigen is expressed on both erythrocytes and ECs, the initial experimental interrogation of the Duffy knockouts revealed no specific clues regarding
its function on ECs. Luo et al. (125) described a reduction of lipopolysaccharide
(LPS)-induced neutrophil infiltration into the peritoneal cavity, lungs, and gut of
Duffy antigen–knockout mice. Conversely, Dawson et al. (126) observed an increase in neutrophils in the lungs and hepatic sinusoids after LPS application.
Curiously, these conflicting findings may both result from lack of Duffy antigen
on erythrocytes. Apparently, in addition to its accepted function as a chemokine
sink, Duffy antigen may serve also as a chemokine reservoir. Injected chemokines
disappear from plasma of Duffy antigen–deficient mice, whereas wild types maintain their chemokine plasma levels much longer (124, 127). Consequently, Duffy
antigen on erythrocytes may act as a chemokine buffer, reducing in some settings
the plasma levels of chemokines while maintaining them in others, thus indirectly
influencing leukocyte emigration.
However, Duffy antigen expressed by ECs may also directly impact chemokineinduced leukocyte emigration. Chemokine binding and uptake by venular ECs is a
function of their Duffy antigen expression (124). Duffy antigen supports transport
of chemokines by ECs and epithelial cells in vitro, leading to enhanced leukocyte
transmigration across the barriers formed by these cells (124, 128). Importantly,
in contrast to the chemokine-scavenging function proposed for D6 (see below),
chemokine internalization by Duffy antigen does not result in their degradation
(124). Finally, in mice that lack Duffy antigen on ECs, but not on erythrocytes, neutrophils exhibit diminished emigration to suboptimal concentrations of chemokines
(124). Cumulatively, these data suggest that by selecting chemokines for EC internalization and transcytosis, Duffy antigen may serve as an editor of Chemokinese
messages destined to appear on the luminal surface. It is not clear if endothelial
Duffy antigen is responsible for these functions alone or in cooperation with heparan sulfate. The latter possibility is supported by reduced CXCL8 association
with ECs in heparatinase-treated human skin (103). There may also be other yet
unknown interceptors involved in EC transcytosis of chemokines. For example,
CCL19, which does not bind to Duffy antigen, is effectively transcytosed and
luminally presented in high endothelial venules (HEV) (129).
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Chemokinese Telecommunication Channels and Their Censor
In addition to distribution within their tissue of origin, chemokines can disseminate
via preformed channels, e.g., afferent lymphatics into the draining lymph nodes
(LN). Here they are channeled by conduit structures (130) to HEV, transcytosed,
and presented on the luminal surface to induce leukocyte recruitment (Figure 3).
This mechanism was demonstrated for CCL2 produced in skin during inflammation
as well as for several other chemokines injected into skin (131, 132). The purpose
of such a long-distance broadcast of formulated Chemokinese messages is possibly
to boost in the LNs the number of cells involved in innate pathogen containment
(see below). However, excessive transmission of inflammatory chemokines may
lead to uncontrolled recruitment of potentially histotoxic leukocytes. A possible
safeguard against this may be the chemokine interceptor D6 (CIPR-2), which is
expressed by lymphatic ECs (133). As D6 internalizes many CC chemokines and
presumably targets them for lysosomal degradation (134), it may function at this
microanatomical location as a censor of the Chemokinese broadcast to the LNs.
This allows only selected chemokines from the periphery to reach LNs unaltered,
whereas others may arrive only after mitigation by D6. Additionally, D6 may serve
as a gatekeeper of leukocyte trafficking through the lymphatics by modifying local
chemokine gradients (124).
CHEMOKINES IN INNATE IMMUNITY
Few functions of Chemokinese are as self-evidently important as its role in orchestrating leukocyte responses during pathogen containment. Infectious microorganisms can directly stimulate chemokine production by tissue dendritic cells (DCs)
and macrophages as well as by many parenchymal and stromal cells. Conserved
microbial pathogen-associated molecular patterns induce chemokines through pattern recognition receptors, such as Toll-like receptors, or the nucleotide-binding
site leucine-rich repeat proteins NOD1 and NOD2 (135, 136).
Endogenous molecules associated with infection and injury, e.g., fibrinogen,
elastase, and defensins, can also signal through pattern recognition receptors to
induce chemokine production (137–139). However, classically the major inflammatory and immunomodulatory cytokines such as IL-1, TNF-α, IFNγ , IL-4, IL-5,
IL-6, IL-13, and IL-17, induced in injury or infection, stimulate through their respective receptors the production of many different chemokines (1–3). Why do
these eloquent exogenous and endogenous alarm signals need to be paraphrased in
Chemokinese? First, such translation amalgamates different signals into one coherent and universally understood message. Also, the translating cells may wield their
interpretational bias and provide chemokine-encoded clues to reveal themselves
and their anatomical residence (140, 141). Chemokines produced in response to
pathogens typically are ligands of CCR1, CCR2, CCR3, CCR5, CXCR2, and
CXCR3. All these receptors engage multiple chemokines, which may be considered “synonymous” insofar as the message they convey through their promiscuous
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receptors is similar. In addition, many of these chemokines can signal through
several different receptors (Figure 1) and therefore are comparable to homonyms,
words with multiple meanings. Synonymy and homonymy of chemokines have euphemistically been branded “chemokine redundancy.” However, chemokines and
their receptors are not truly redundant. Few chemokines carry identical meanings
or are fully interchangeable. This is because of their unique homonymy profiles
(as illustrated by the color bar code in Figure 1) and because of different agonistic properties synonymous chemokines have on the same receptor, i.e., potency,
efficacy, and ability to induce receptor desensitization and internalization. What
is the reason for chemokine synonymy and homonymy, and what function may
such overlapping specificities carry in host defense? We attempt to answer these
questions by comparing the chemokine-driven “cell reflex” in response to infection
with the sensory functions of the CNS.
Sensory and Effector Roles of Chemokinese
Evolution selected GPCR-based systems to serve three of our sensory functions.
Vision, taste, and smell all rely on GPCRs. In case of olphactory detection, single
receptors can engage several different odorants, and a single odorant can bind several different receptors. By combinatorial engagement of approximately 400 different odorant receptors, humans can distinguish several thousand different odors
(142). Similarly, chemokine receptors may fill a sensory function for the immune
system. Different pathogens lead to the production of characteristic fingerprints of
chemokines (143), which are projected onto the luminal surface of venular ECs
where the pathogen is “described” in Chemokinese to the patroling leukocytes.
These telling abstractions of a virus, bacterium, fungus, protozoa, or helmith are
read through the GPCRs, which immediately trigger the “cell reflex,” leukocyte
adhesion, and emigration. The overlapping ligand and receptor specificities within
the chemokine system may not only serve the robustness of the leukocyte response
(144), but also, by analogy with olfactory perception, be required for increasing
the combinatorial finesse of pathogen portrayal and generation of diversity in the
leukocyte response to it. Further diversity may be provided by classical chemoattractants and migration modifiers derived from other endogenous mediator systems
(e.g., activated complement and pro- or anti-inflammatory lipids) or directly from
pathogens. The leukocytes recruited by this cocktail of agonists divide among them
the tasks of pathogen containment by different microbicidal means (143): amplification and fine-tuning of leukocyte recruitment by producing or inducing further
chemokines (145); pathogen acquisition, processing, and initiation of the most pertinent adaptive immune response (146); and setting the stage for tissue repair. As
reviewed recently (143, 147), mice that are deficient for different chemokines and
chemokine receptors may have compromised innate immunity to pathogens. Conversely, animals overexpressing chemokines may, in some settings, be protected
from infection (148).
There are many fine nuances in the assortment of leukocytes that become mobilized in response to different pathogens (143), but with considerable
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oversimplification the reactions can be categorized as either type 1 or type 2, depending on the cytokines and chemokines produced and the involvement of polar
sets of effector lymphocytes and leukocytes. CCR1, CCR5, CXCR3, and CXCR6
and their ligands are associated with type 1 responses, whereas CCR3, CCR4,
and CCR8 and their ligands are associated with type 2 responses. These dichotomous chemokine pathways are also reflected in two main routes of pathogenesis in
chronic inflammatory diseases. The discovery of Toll-like receptors made it clear
how microorganisms can directly induce type 1 chemokines (135). Recent results
showed that innate type 2 responses are also directly stimulated by pathogens
(149). Thus, the amount and composition of chemokines that are generated by infected individuals in response to certain pathogens can determine the type of innate
immune response. This may happen, at least in some settings, without the involvement of adaptive immunity, which, however, may further amplify the preexisting
type 1 or type 2 bias. This differentiation can also be influenced by chemokines.
The presence of CCL3 or CCL2 at the time of antigen challenge of naive T cells
induces Th1 and Th2 differentiation, respectively (150). Such chemokine influence was confirmed in CCL2-deficient mice, which have reduced Th2 responses
(151). Conversely, mice deficient for CCR2, the only known CCL2 receptor, have
impaired Th1 responses (152), owing to reduced monocytes trafficking to sites of
inflammation (153). How this apparent discrepancy between the Th1/Th2 profiles
in CCL2 and CCR2 knockout mice may be reconciled and several alternative hypothetical mechanisms of chemokines determining the T helper bias are discussed
in a recent review (154).
Teleologically, chemokines induced by a pathogen should select a panel of
leukocyte types with effector functions that are tailored to eliminate the invader.
This is not always the case. Because pathogens evolve rapidly under the selection pressure from our defenses, they may escape the effector functions of leukocytes recruited by chemokines. Some infectious microorganisms even exploit the
chemokine-driven defenses in their pathogenesis strategies, and the effector functions of leukocytes may contribute to the unfavorable disease outcome (155). The
recruited leukocytes may be used as safe havens, vehicles to disseminate, or Trojan
horses to get access to organs that are difficult to reach. No other pathogen class
uses and abuses Chemokinese as brazenly as the viruses.
Chemokinese as a Foreign Language: The Virokinese
Successful warfare requires the communication language to remain secret. Higher
organisms failed this mission during the billion years’ war they have waged against
viruses. Endowed with a remarkable ability to attain genetic information, some
viruses have broken the code of Chemokinese and learned how to use it in their
diverse survival stratagies. For example, HIV masquerades as a “chemokine” and
uses chemokine receptors to promote its fusion with target cells. Pox and herpes
viruses encode in their genomes chemokine receptors that are expressed by the
infected cells. This allows the host chemokines to drive the infected cells into
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remote sites for undisturbed cycles of replication and infectivity. Alternatively,
viral chemokine receptors may induce uncontrolled cell proliferation, providing
new cell targets for virus replication. Herpes viruses produce chemokines with
agonist and antagonist features. Agonists may lure their potential targets or skew
the host responses toward Th2, which renders antiviral defenses futile. Antagonists
may simply derail the migration of immune cells. Finally, viruses can produce
chemokine binding proteins that interfere with the Chemokinese communication of
the host by inhibiting either receptor binding of chemokines or their immobilization
by GAGs, or both. For further details on the fascinating world of Virokinese, we
refer the reader to several recent reviews (156–158).
Unique Meanings of Chemokines
In contrast to synonymous and homonymous chemokines, there are chemokinereceptor pairs that appear to be monogamous, including CXCR4-CXCL12,
CXCR5-CXCL13, CCR6-CCL20, CCR8-CCL1, and CCR9-CCL25. The majority of these include the constitutively expressed “homeostatic” chemokines. There
are also several homeostatic two ligands/one receptor “relationships”: CCL19 and
CCL21 bind to CCR7, CCL17 and CCL22 to CCR4, and CCL27 and CCL28
to CCR10. These pathways are mainly involved in directing the tissue-specific
migration of leukocytes between and within primary, secondary, and tertiary lymphoid organs. They are also required for the development of lymphoid organs and
the establishment of functional microenvironments within them. The contribution
of homeostatic chemokines to lymphorganogenesis has been reviewed recently
(159). However, the division into inducible and homeostatic chemokines is by no
means absolute. Homeostatic chemokines are upregulated in inflammation and
are responsible for the recruitment of leukocytes, specifically into chronic lesions
where they can promote the formation of ectopic lymphoid structures (160–163).
Many inducible chemokines are also produced homeostatically, and some are secreted into normal colostrum, milk, eccrine sweat, saliva, and tears (164–166).
Such secretion may take advantage of defensin-like direct antimicrobial properties that have been described for several chemokines, including CXCL4, CXCL7,
CXCL9, CXCL10, CXCL11, CCL5, and CCL28. Also, several β-defensins are
full agonists of CCR6. For more on this subject, see the review by Yang et al.
(166a) in this volume.
As discussed in detail below, homeostatic chemokines and their apposite receptors determine and restrict the migratory paths of lymphoid cells. However, a
single signal can elicit diverse functional responses in different cells. For example,
CXCL12 induces the migration of primordial germ cells and lateral sensory organ
cells in developing zebrafish and critically contributes to embryonal hematopoeisis, vasculogenesis, and cardiogenesis, as well as the development of the cerebellum and dentate gyrus in mice. Postnatally, CXCL12 drives the migration of
hematopoietic and EC progenitors required for bone marrow homing and neovasculogenesis, respectively. It is also involved in inflammatory recruitment of diverse leukocytes. In tumors of various origins, CXCL12 promotes cell survival and
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induces metastasis. In the brain, where CXCL12 has apparently originated (167),
it attracts microglia, stimulates astrocytes, elicits postsynaptic currents in Purkinje cells, and promotes pain perception. Given all these diverse effects, CXCL12
might mean “Just do it!” in Chemokinese.
Chemokines in Inflammatory Diseases
To a hammer every problem looks like a nail; to an immune system every problem
looks like an infection. The downside of carrying stencil templates for highly effective alarm messages is that they may be applied to innocuous situations that are interpreted as danger, such as chronic inflammatory and autoimmune diseases (168).
Whatever the primary triggers may be, chemokines appear in the lesions of debilitating human diseases such as rheumatoid arthritis, bronchial asthma, multiple
sclerosis, type I diabetes, arteriosclerosis, and inflammatory bowel disease. The
mechanisms of chemokine induction are probably similar to those in response to
pathogens. Chemokines recruit leukocytes that, through their individual effector
functions, perpetuate the vicious disease cycles by causing tissue damage, providing further inflammatory signals, and propagating the molecular sequences of
autoimmunity (169). A new generation of anti-inflammatory drugs is expected
to emerge from current pharmacological efforts to target chemokines and their
receptors (170–172a).
But which chemokines or receptors to target? For some diseases the targets
may be as self-evident as CCR9 is in inflammatory bowel disease. However, in
rheumatoid arthritis at least 12 different chemokines have been suggested as playing pathoetiological roles. This implicates the involvement of at least nine distinct
receptors. The chemokine involvement is similarly complex in other inflammatory diseases. Curiously, the alternative elimination of a single chemokine or the
silencing of a single receptor may scramble the Chemokinese message in an inflammatory disease sufficiently to break the backbone of pathogenesis. This has been
demonstrated by the alleviation of disease-specific parameters in experimental
and clinical arteriosclerosis in mice and humans deficient for either CCL2, CCR2,
CXCR2, or CX3CR1 (173–176), and for CCR2, CCR5, or CX3CR1 (177, 178),
respectively. Yet in theory, removing nonessential chemokines may leave the message intact, similar to the way that in Semitic languages the meaning of a word is
clear without registering the vowels. Chemokine- or chemokine receptor–deficient
mice and human polymorphisms that result in chemokine pathway deficiencies,
e.g., CCR5132, provide possibilities to explore both of these scenarios and have
been reviewed in detail recently (147, 170–172).
CHEMOKINES IN ADAPTIVE IMMUNITY
The ability to use language is a skill that keeps evolving throughout a person’s
life. As we accumulate experiences and our frame of reference changes, so does
our interpretation of language. Many immune cells, particularly T cells, undergo
analogous changes in their comprehension of Chemokinese (172a, 178a). These
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changes, reflected by characteristic expression of chemokine receptors, accompany
every major T-cell differentiation event. The following examples highlight how
different immunological tasks determine the capacity of T-cell subsets to read and
interpret chemokine signals.
Naive Lymphocyte Seeking Mature DC: Matchmaking
in Chemokinese
The single-minded mission pursued by naive T cells is to find a cognate antigen.
However, a primary T-cell response is only induced when the antigen is presented
by mature DCs (179). This necessitates that these two dissimilar cells unite in an
event orchestrated by chemokines, but not before DCs have acquired antigen, a
process efficient only prior to their maturation. Immature DCs and their precursors
develop in the bone marrow and migrate into peripheral tissues and secondary
lymphoid organs. Normal mouse LNs contain at least six distinct DC subsets with
different immunological activities, tissue distribution, and trafficking properties
(180). Some DCs (e.g., plasmacytoid DCs) are thought to home into LNs from the
blood (see below), whereas others originate in peripheral sites and take residence
in LNs by way of afferent lymph vessels. Peyer’s patches (PPs) and the spleen do
not have afferent lymph vessels, so all resident DCs have probably homed in there
from the blood. Immature DCs in LNs, PPs, and the spleen collect and process
lymph-borne, intestinal, or blood-borne antigens, respectively. Their counterparts
in peripheral tissues acquire antigens that arise locally or enter through the body’s
surfaces. Another source of DCs is circulating monocytes, which express numerous
receptors for inflammatory chemokines and other chemoattractants and which
accumulate at sites of acute inflammation and in LNs that receive afferent lymph
from inflamed tissues (132, 181, 182).
Irrespective of the site where they capture antigens, DCs must migrate into
the T-cell area of lymphoid tissues and assume a fully mature phenotype before
they can “educate” naive T cells (172a, 178a, 179). DC maturation induces several
critical changes, including the pattern of chemokine receptor expression (179,
182–184).
Maturing DCs must downregulate most of their initial chemokine receptors
and upregulate CCR7 to present antigens to T cells. CCR7 allows both tissueresident and monocyte-derived DCs in peripheral sites to enter afferent lymphatics,
which express CCL21 and possibly CCL19 (185). DC responsiveness to lymphatic
CCL19 is supported by a second autocrine signal in the form of cysteinylated
leukotrienes (186). There is still uncertainty about the precise step(s) at which
CCR7 ligands function. They may assist DCs in finding lymph vessels and/or
enable DCs to enter these vessels. CCR7 ligands are also essential in allowing
DCs that have entered the subcapsular sinus or reside in the superficial cortex in
LNs to migrate into the T-cell area in the deep cortex (187). Here, they form a
welcoming committee that presents antigen to T cells that continuously enter this
region via HEV. Recent measurements indicate that a single DC in an LN gets in
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touch with as many as 500 different T cells per hour (188). However, in the vast
majority of their visits to lymphoid organs, T cells fail to find “their” antigen, and
after a few hours they return to the bloodstream to try their luck elsewhere.
Circulating naive T cells express several essential traffic molecules, including
the adhesion molecules L-selectin, LFA-1, and α4ß7 integrin, and two chemokine
receptors, CCR7 and CXCR4. This restricted repertoire of traffic molecules is
tailored for interactions with the specialized microvessels in lymphoid tissues and
keeps naive T cells from straying into other regions of the body. For the purpose
of lymphocyte trafficking, CCR7 and its ligands CCL19 and CCL21 are essential
(189). CCL21 is synthesized in HEVs (131, 190), the principal port of lymphocyte
entry into LNs and PPs (191), and by lymphatic ECs and some interstitial cells in
T-cell areas of lymphoid organs. CCL19 has also been claimed to be generated by
lymphatic endothelium (186) and is produced by DCs and probably other cells in
T-cell areas, but not in HEVs. As discussed above, lymph-borne CCL19 can be
transcytosed from the extravascular compartment to the luminal surface of HEVs,
where it is presented to lymphocytes together with CCL21 (129). The genes for
CCL19 and the HEV-expressed form of CCL21 are deleted in a strain of mice
called paucity in lymph node T cells (plt/plt) (187). Consequently, naive T cells
undergo rolling via L-selectin, the chemoattractant-independent first step in the
homing cascade, but they do not undergo activated integrin-dependent arrest in
LN HEV of plt/plt mice (131). However, intracutaneous injection into plt/plt mice
of either CCL19 or CCL21 leads to chemokine translocation to HEV in draining
LNs and reconstitution of integrin activation and T-cell homing (129, 131). Thus,
either of the two CCR7 agonists is sufficient for integrin activation on rolling T cells
in HEV, but HEV-expressed CCL21 probably provides the predominant signal.
The situation is somewhat more complex for naive B-cell homing. Compared
with the migration of T cells, B-cell migration to LNs and PPs of plt/plt mice is
much less compromised (192). This is because rolling B cells in HEVs can activate
integrins and arrest not only in response to CCR7 agonists, but also upon CXCR4
triggering by CXCL12, which is presented in some HEVs in the outer cortex (193).
In PPs, another B cell–specific chemokine pathway can induce moderate sticking
via CXCR5 on B cells and CXCL13, which is selectively expressed in PP HEV
segments that are in contact with B follicles (193). In contrast, CCL21 is only
presented by HEVs in the interfollicular T-cell area of PPs (194).
The physiological role of CXCR4 and its ligand CXCL12 in trafficking of lymphocytes, especially of naive T cells, is unresolved. Mice with a genetic deficiency
in either molecule are not viable (195, 196), but using bone marrow chimeras, researchers have performed a few studies with CXCR4-deficient hematopoietic cells
(193, 197). One study found a modest role for CXCR4 in T-cell sticking in LN
HEV of plt/plt mice (193). This work was carried out with unfractionated T cells,
leaving open the possibility that the T cells that responded to CXCL12 in HEV
were LN-homing memory T cells. Indeed, studies that have specifically analyzed
naive T cells found that, although CXCL12 induced chemotaxis in vitro, it failed
to trigger integrin-mediated arrest in vivo or to reconstitute naive T-cell homing
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in plt/plt mice (131, 161). Thus, there appears to be a dissociation in the type of
response that is elicited by CXCL12 in different CXCR4-expressing lymphocyte
subsets. B cells (and probably some memory T cells) respond with chemotaxis
and rapid integrin activation, whereas naive T cells undergo only chemotaxis. An
additional level of complexity is introduced by the finding (discussed above) that
most T cells are attracted by low to modest concentrations of CXCL12, but a subset
migrates away when exposed to a high concentration of CXCL12 (46).
Lymphocyte homing to the spleen is a special case because no specific adhesive
interactions with ECs appear to be required (198). However, lymphocytes must
migrate into the peri-arteriolar lymphoid sheath (PALS) after extravasating from
marginal-zone sinuses in the red pulp. To find their proper place in the PALS, B- and
T-cells use integrins (62) and depend on CXCR5 and CCR7 to sense chemokine
gradients that guide them into B follicles and the T-cell area, respectively. A genetic
deficiency in either receptor or their respective ligands or inhibition of chemokine
signaling by pertussis toxin inhibits lymphocyte migration into the PALS and
results in severely disorganized white pulp cords (189, 199, 200).
B cells that diapedese across HEV in LNs must traverse the T-cell area to reach
B follicles. This directed migration is mediated by CXCR5 on the migrating B cell
and CXCL13, which is generated in B follicles (200, 201). Once they have reached
the follicles, most B cells continue to wander in random directions within the B-cell
compartment (202). Similarly, T cells that home into LNs display chemokinesis
when viewed both by multiphoton microscopy in freshly excised LNs in vitro
and by intravital microscopy in vivo (202, 203). The factor(s) that stimulate Band T-cell chemokinesis in their respective compartments remain to be identified.
Mature DCs express several chemokines that might attract T cells, and in vitro
studies have shown that DCs can stimulate random T-cell migration in collagen
gels (204). Whether DCs or DC-derived secreted factors are required for interstitial
lymphocyte migration in LNs has not been determined.
Effector and Memory Cell Migration: Staying on Track
in the Tower of Babel
Full-fledged activation induces T-cell proliferation followed by acquisition of effector functions. Whether effector cells differentiate to support primarily cytotoxic, interferon-γ -driven (type 1) responses or humoral, IL-4-dependent (type 2)
responses depends on a variety of factors that have been reviewed elsewhere (205,
206). Irrespective of their specific flavor, effector cells are entrusted with the critical task of eliminating the source of their cognate antigen. To do this, T cells must
develop a sophisticated and diversified understanding of Chemokinese. One of the
earliest changes is seen on activated CD4 T cells, which upregulate CXCR5 and
reduce CCR7 expression. This allows them to migrate toward the edges of B follicles to provide help to B cells and promote germinal center formation (207–210).
Conversely, antigen-stimulated B cells acquire responsiveness to CCL19, which
drives them toward the T-cell area.
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An equally important requirement is that effector cells gain efficient access to
nonlymphoid tissues that contain their cognate antigen. Typically, these tissues
experience some form of distress due to, for example, an infection. The ensuing
innate immune response leads to local production of inflammatory chemokines
and enhanced expression of adhesion molecules on venular ECs (211, 212). Thus,
effector cells upregulate adhesion molecules and chemokine receptors that allow
them to migrate to sites of inflammation (213, 214). As discussed above, some
pathogens can only be eliminated by type 1 responses, whereas others require a
type 2 response. The cytokines released by either effector subset suppress each
other’s effects. To avoid an immunological stalemate, Th1 and Th2 cells obey
different traffic signals and express distinct patterns of chemokine receptors (reviewed in 215). In particular, CCR5 and, less conspicuously, CXCR3 predominate
on Th1 cells, whereas CCR4 and CCR8 are primarily found on Th2 cells. It has
also been reported that CCR3 and CXCR4 are preferentially expressed on Th2
cells, but this is somewhat controversial. The chemokines that stimulate Th1 cells
are induced by IFN-γ and suppressed by IL-4, which induces a chemokine milieu
that preferentially attracts Th2 cells.
While distinct chemokine receptor patterns are clearly induced on in vitro–
polarized effector Th cells, the situation in vivo is often less clear-cut. One major
modulating factor during the induction of effector cells in lymphoid organs is
whether an antigen is encountered in a cutaneous or intestinal context (216). In a
sense, the skin and the intestine use different dialects of Chemokinese, even in the
absence of inflammation. Thus, dermal postcapillary venules present CCL17 and
CCL27 on their luminal surface. Effector cells that are generated in response to
cutaneous antigens express the respective counter-receptors, CCR4 and/or CCR10,
and expression of at least one of these is required for homing into the skin (217).
The analogous constitutive chemokine in the small intestine is CCL25, whose receptor, CCR9, is expressed on thymocytes and naive CD8 T cells [CCL25 is also
expressed in the thymus, where it may play a role in the generation of naive T cells
(218, 219)]. Effector T cells that are stimulated by DCs from gut-associated lymphoid tissues maintain CCR9 expression and responsiveness to CCL25, whereas
T cells lose responsiveness to CCL25 when activated by DCs from other lymphoid organs (220). Indeed, DCs in PPs and mesenteric LNs acquire a lymphoid
organ-specific flavor that allows them to target effector cells to the small intestine,
the site most likely to contain a cognate antigen (220, 221). This tissue-specific
imprinting is mediated, in part, by the DCs’ ability to make T cells perceptive to
regional chemokines. Whereas CCR9 or CCR4/CCR10 expression is a necessary
component for effector cell recruitment to the small bowel or skin, respectively,
their presence alone is not sufficient for homing. T cells must additionally express appropriate adhesion molecules that interact with organ-specific endothelial
addressins (212).
Recent work has shown that antibody-secreting plasma cells also consist of different subsets that are characterized by distinct chemokine receptor patterns and
differential regional distribution (222). Most long-lived IgG-producing plasma
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cells reside in the bone marrow. These cells depend on CXCR4-CXCL12 to reach
this site. In contrast, IgA-producing plasma cells are targeted to mucous membranes. A subset of these cells expresses CCR9 and, like small bowel–tropic effector T cells, migrates to the small intestine. However, CCR9 is not involved
in targeting lymphocytes to the colon because CCL25 is not expressed in the
large bowel. IgA-producing plasma cells use CCR10 to home into the colon and
other mucosal sites, which express the CCR10 ligand CCL28 (223). However,
T cells do not appear to use CCR10 to enter the colon. The chemokine pathways for effector T-cell migration to this and other anatomic regions remain to be
identified.
For the purpose of this discussion, effector cells are defined as arising in response to a recent antigenic stimulus, exerting immediate effector activity upon
T-cell receptor stimulation, and being short-lived; whereas memory cells have been
exposed to antigen in the more distant past, are long-lived, and confer enhanced
protection against recall antigens. Memory cells are not a homogenous population, in particular with regard to chemokine receptor expression. One important
distinction is the presence or absence of CCR7 (224). Most CCR7+ memory cells
also express L-selectin and are thus able to home into LNs, whereas CCR7– memory cells do not express L-selectin and cannot home into any secondary lymphoid
organ, except the spleen (214, 225). The CCR7+ and CCR7– subsets have been
termed central memory (TCM) cells and effector memory (TEM) cells, respectively
(224). TEM cells owe their name to their ability to mount rapid effector responses
upon rechallenge and to their repertoire of traffic molecules that resemble effector
cells (224). Given the diversity of effector cells’ migratory specificities, it is not
suprising that TEM cells also fall into several subcategories that express homing receptors for skin, gut, or neither (226). Indeed, following antigen challenge in vivo,
memory cells can be found lodging in multiple nonlymphoid sites throughout the
body (227, 228).
TCM cells have arguably the broadest migratory spectrum of any T-cell subset
because they express both CCR7 and receptors for inflammatory chemokines (214,
224). Thus, TCM cells migrate efficiently to lymphoid tissues as well as to sites
of inflammation (214). Compared with TEM cells, they also have the highest proliferative potential and confer superior immune protection (229, 230). TCM cells
can arise directly from naive T cells (225, 229, 231) or from TEM cells (230). In
the latter case, CCR7 expression is biphasic, i.e., high expression is seen in naive
T cells, which become CCR7– during the effector stage and retain this phenotype
while standing guard as TEM cells in peripheral tissues. At some stage, TEM cells
begin to re-express CCR7, which might allow them to enter local lymphatics and
migrate to LNs (232). It is not clear whether these cells continue their journey
by recirculating exclusively through lymphoid organs or retain peripheral homing
capacity as well. However, the latter scenario is favored by the observation that
many circulating memory cells with skin- and gut-homing phenotypes also express
CCR7 (233).
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SEMANTICS OF CHEMOKINESE
Like words in human languages, chemokines have no inherent semantic value.
Their meaning is decoded by the compulsory presence of the apposite receptors
and depends largely on the responding cell’s nature and nurture, i.e., its genetically
governed functional program and environmental signals. It is clear from the example with CXCL12 that the same chemokine may have dissimilar meanings for
cells of different lineages. Curiously, the meaning of a chemokine for cells of the
same lineage may also vary. For example, CXCL12 signaling through its receptor
on T cells may result, depending on the dominance of either p38 MAPK or Akt in
signal transduction, in a pro- or antiapoptotic signal, respectively (234). We have
already discussed the dramatic change of chemokine meaning depending if the
chemokine is either immobilized on the EC surface (pro-emigratory) or soluble in
plasma (anti-emigratory). The following examples show how chemokine meaning
is changed by the simultaneous presence of different chemokines, by chemokine
processing in limbo between their secretion and perception, and by concomitant
activation of the responding cells.
Semantic Shift by the Presence of Different Chemokines
Individual chemokines may dramatically modify each other’s effects in several
different ways and at different levels. Many cells possess multiple chemokine receptors and are exposed to their diverse ligands simultaneously or sequentially.
How do combinations of dissimilar chemokines work and what is the outcome?
How may leukocyte responses be influenced by different spatial and temporal
sequences of exposure to chemokines or by the direction and steepness of their
gradients? The answers to these questions of Chemokinese syntax are still sketchy
and are largely based on extrapolations of the pioneering work by Foxman et al.
(235, 236). Apparently, leukocytes can maintain a memory of earlier chemokine
exposure, and by comparing it with a newly encountered gradient, they can navigate in simultaneous and sequential gradients of homologous and heterologous
attractants (235, 236). One result of a cell’s exposure to simultaneous conflicting
gradients may be an amalgamation of signals and compromise responses along the
new integrated vector gradient (idiomatic gradient perception). The other possible
outcome is hierarchical prioritization of gradients with the prospect of subdominant
signals being silenced, perhaps owing to a heterologous receptor desensitization
and downregulation (237). However, there are also examples of chemokines synergistically potentiating each other’s effects by priming the responding cells (238)
through heterodimerization of their receptors (57) or by forming heteroaggregates,
which may create a new, more powerful meaning.
In addition, chemokines can directly influence each other’s receptor binding
because chemokines with agonistic activity for one receptor may be antagonists
for another. Such chemokine “antonyms” include CCL7, that acts as an antagonist
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on CCR5 (239); all three CXCR3 agonists that function as CCR3 antagonists
(9, 240); CCL18, an agonist for an unidentified receptor on T cells that is also
a CCR3 antagonist (241); and two eotaxins, CCL11 and CCL26, that are CCR2
antagonists (47, 242). In addition, CCL11 shows high-affinity binding to CXCR3
but does not signal and does not compete for binding with other ligands. Thus,
CXCR3 may function as a CCL11-sequestering decoy (9). Undoubtedly, more
examples of chemokine antagonism will emerge in the future.
Proteolytic Processing of Chemokines
Many chemokines are processed enzymatically after their secretion, leading to
changes in their agonist properties. For example, dipeptidyl aminopeptidase IV
(CD26) can cleave the two N-terminal amino acids of chemokines with proline, hydroxyproline, or alanine in the second N-terminal position, and it can dramatically
change the perception of these chemokines by their receptors (243). Other proteases may also specifically cleave chemokines with either up- or downregulation
of their agonistic properties and potential induction of antagonism. Examples of
semantic shifts induced by proteolytic digestion of chemokines are listed in Table 1.
Semantic Shift by Functional Coupling and Uncoupling
of Chemokine Receptors
Another way of modulating chemokine perception is through cytokine-dependent
regulation of receptor expression or its coupling to signal transduction. This circumstance was not appreciated at the time of the discovery of the first chemokines.
Initially it was postulated that there was a profound functional dichotomy between
CC chemokines on one hand and CXCL8 and related chemokines that share the
ELR tripeptide motif on the other hand. The latter were thought to affect neutrophils
but not monocytes, whereas the former stimulate monocytes but not neutrophils.
However, subsequent work has shown that monocytes express both functional
CXCL8 receptors (244, 245), can migrate in response to this chemokine (246),
adhere firmly under shear flow in response to CXCL8 and other CXCR2 ligands
(247–249), and localize to inflammatory lesions by means of CXCR2 (175, 250).
The apparent disagreement of these data with the initial observations of the exclusive neutrophil activity of CXCL8 was elegantly resolved by a report showing
that cytokines, IL-4 and IL-13 in particular, can increase the expression of both
CXCR1 and CXCR2 on the surface of monocytes and couple them to productive
signal transduction pathways (251). Similarly, IFNγ stimulation of neutrophils
upregulates CCR3 and renders these cells responsive to CCR3 ligands, which are
commonly thought of as classical eosinophil agonists (252). Conversely, the induction of CCR3 on B cells by IL-2 and IL-4 makes these cells susceptible to
apoptotic signals through CCL11 (253). There are many other cases of downregulation or upregulation of chemokine receptor expression and function by cytokines
and other stimuli. For example, as discussed above, immature “inflammatory” DCs
lose CCR1, CCR2, and CCR5 in the process of maturation and start to express
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913
TABLE 1 Examples of semantic shift induced by proteolytic digestion of chemokines
Chemokine
Enzyme
Processed forms
Receptor/Outcome
CXCL7
Elastase
Chymotrypsin
CXCL7 (25–94)
CXCL7(23–94)
CXCR2 agonism↑
CXCL8
Many
CXCL8(3–79)
CXCL8(8–79)
CXCL8(9–79)
CXCL8(10–79)
CXCL8(11–79)
With each step CXCR1
and CXCR2 agonism↑
CXCL9
CD26
CCL9(3–103)
CXCR3 agonism↓
CXCR3B(?)agonism→
CXCL10
CD26
CCL10(3–77)
CXCR3 agonism↓
CXCR3B(?)agonism→
CXCL11
CD26
CCL11(3–73)
CXCR3 agonism ↓
CXCR3B(?) agonism→
CXCL12
CD26
CXCL12(3–68)
CXCR4 agonism↓ desensitization→
CXCL12
Elastase
MMP-1, -2, -3,
-9, -13, -14
Cathepsin G
CXCL12(4–67)
CXCL12(5–67)
CXCL12(6–67)
CXCR4 agonism↓
CCL2
MMP-1, -3
CCL2(5–76)
CCR2 agonism↓ antagonism↑
CCL3L1
CD26
LD78β(3–70)
CCR1 and CCR5 agonism↑
CCL4
CD26 (?)
CCL4(3–69)
CCR1agonism↑ CCR5 agonism→
CCL5
CD26
CCL5(3–68)
CCR1 and CCR3 agonism↓
CCR5 agonism→
CCL7
MMP-1, -2, -3,
-13, -14
CCL7(5–76)
CCR1, CCR2, CCR3 agonism ↓,
antagonism ↑
CCL8
MMP-3
CCL8(5–76)
CCR2 agonism↓, antagonism ↑
CCL11
CD26
CCL11(3–74)
CCR3 agonism↓ desensitization →
CCL13
MMP-1, -3
CCL13(4–75)
CCL13(5–75)
CCL13(8–75)
CCR2, CCR3 agonism↓,
antagonism ↑
CCL14
Serine proteases
CCL14(9–74)
CCR1, CCR5, CCR3 agonism ↑
CCR7 (254). LPS treatment can accelerate this process. In contrast, simultaneous
LPS plus IL-10 treatment retains the inflammatory chemokine receptors and inhibits CCR7 induction (8). In addition, the combination of IL-10 plus LPS changes
the signal coupling of CCR1, CCR2, and CCR5 and renders them nonsignaling in
response to their cognate ligands, which, however, are internalized and sequestered.
Thus, these receptors have transformed into chemokine-scavenging decoys (8).
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CONCLUSIONS
Chemokines are molecular symbols that make up cell messages and, depending
on the biological context, can have different meanings. Chemokines are perceived
and acted upon by many different cell types. Each interpretation, each reaction,
mirrors as much of the responding cell’s nature as it reflects on the chemokine
itself. Our efforts to understand Chemokinese exemplify the difficulties faced by
the researchers in the postgenomic era. The human genome, “the book of life,” is
open; we can read it and one day will surely understand. Decoding the complete
meaning of Chemokinese is going to be a similarly monumental task as has been
the deciphering of the ancient Egyptian hieroglyphs. Our success will open the
door for new disease remedies that, unlike our current drugs, which silence cells
by gag order, will work more as cell speech therapy.
ACKNOWLEDGMENTS
We thank Pius Loetscher, Rob Nibbs, Dieter Maurer, Tamás Schweighoffer, Charles
Mackay, and Lesley Silberstein for carefully reading the manuscript and Joe Moore
for superb editorial assistance. Research was supported by NIH grants AR42689,
HL62524, HL54936, and HL56949 to U.H.v.A.
The Annual Review of Immunology is online at http://immunol.annualreviews.org
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Figure 1 Human chemokines and their receptors. Solid and dashed lines connect
receptors with their agonists and antagonists, respectively, and are color coded to
correspond with the colors of individual receptor hubs. The dashed-dotted line that
connects CXCR3 with CCL11 represents a nonagonist-nonantagonist binding interaction. The bars next to individual chemokine numbers reflect the colors assigned to
their apposite receptors.
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Figure 2 Signaling from chemokine receptors, through activation of four small GTPases, to leukocyte chemotaxis and integrin activation.
Red arrows lead to the activation of Rac, required for the actin polymerization at the pseudopod; green arrows lead to the activation of
Cdc42, required for the establishment of orientation machinery at the pseudopod; blue arrows lead to the activation of Rho, required for
the retraction of the uropod; brown arrows lead to the activation of Rap, required for inside-out signaling of integrins. All abbreviations
and individual steps are described in the text.
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See legend on next page
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VON ANDRIAN
Figure 3 Suggested involvement of interceptors Duffy antigen and D6 in chemokine
interactions with ECs of tissue venules, afferent lymphatic vessels, and high endothelial
venules (HEV) of draining lymph nodes (LN). Chemokines (green and blue kernels) diffuse into the bloodstream through the junctions between ECs (a). Alternatively, CXC and
CC chemokines are internalized and transcytosed by interceptor Duffy antigen (CIPR-1) on
ECs (b). This optimally supports their luminal presentation by GAGs to the chemokine
receptors (CKR) on rolling leukocytes (c), resulting in activation of integrins, firm leukocyte adhesion, and emigration. Conversely, chemokines in plasma stimulate the free-floating leukocytes (d), resulting in deactivation of their emigratory responsiveness. Plasma
chemokines bind to Duffy antigen on erythrocytes (e), which serves both as a sink as well
as a long-term depot for chemokines in the blood. In addition, chemokines may diffuse
through the afferent lymphatics into the draining LNs (f) where, via a conduit system, they
reach the HEV, are transcytosed and presented on the luminal surface (g), and can recruit
pertinent leukocytes into the LN. Chemokine interceptor D6 (CIPR-2), expressed by lymphatic ECs, binds a subset of CC chemokines, internalizes and targets them for degradation
(h), and thus offsets the remote control of leukocyte recruitment into the LN by the
chemokines derived at the periphery.