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IL-17 Family Cytokines and
the Expanding Diversity of
Effector T Cell Lineages
Casey T. Weaver,1,2 Robin D. Hatton,1
Paul R. Mangan,2 and Laurie E. Harrington1
1
Departments of Pathology and 2 Microbiology, University of Alabama at
Birmingham, Birmingham, Alabama 35294; email: [email protected]
Annu. Rev. Immunol. 2007. 25:821–52
Key Words
First published online as a Review in Advance on
January 2, 2007
adaptive immunity, innate immunity, Th1, Th2, Th17, IL-17,
IL-23, IL-25, IL-27, TGF-β, IL-6
The Annual Review of Immunology is online at
immunol.annualreviews.org
This article’s doi:
10.1146/annurev.immunol.25.022106.141557
c 2007 by Annual Reviews.
Copyright All rights reserved
0732-0582/07/0423-0821$20.00
Abstract
Since its conception two decades ago, the Th1-Th2 paradigm has
provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate
into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines
produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately
matching adaptive immunity to frontline cues of the innate immune
system. Owing in part to the rapid identification of novel cytokines
of the IL-17 and IL-12 families using database searches, the factors
that specify differentiation of a new effector T cell lineage—Th17—
have now been identified, providing a new arm of adaptive immunity
and presenting a unifying model that can explain many heretofore
confusing aspects of immune regulation, immune pathogenesis, and
host defense.
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INTRODUCTION
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Adaptive immunity evolved to enhance the
eradication of pathogens in vertebrates, layering antigen specificity and memory onto
preexistent innate immunity. A hallmark of
adaptive immunity is the antigen-driven differentiation of clonally restricted lymphocyte precursors into effector cells of enhanced
functional potential. The differentiation of
naive T cells into effector T cells is characterized by the acquisition of new profiles
of cytokine production and is largely guided
by cytokines produced by pathogen-activated
cells of the innate immune system. Many of
the key advances in our understanding of effector T cell development and function have
therefore been tied to advances in cytokine
biology. This was so for the discoveries that
drove the conception and establishment of the
Th1-Th2 paradigm (1) and has been so of recent discoveries leading up to the identification and characterization of a new lineage of
effector CD4 T cells, Th17.
The Th17 lineage has emerged from discovery of a new family of cytokines [the interleukin (IL)-17 family], addition of new
members of a cytokine family with wellestablished effector T cell ties (the IL-12
family), and identification of new activities
for the pleiotropic cytokines, transforming
growth factor (TGF)-β and IL-6. Th17 cells
appear to have evolved as an arm of the adaptive immune system specialized for enhanced
host protection against extracellular bacteria and some fungi, microbes probably not
well covered by Th1 or Th2 immunity, that
evolved to enhance clearance of intracellular
pathogens and parasitic helminthes, respectively. Although Th17 cells represent the first
new class of effector CD4 T cells to be defined since the original description of Th1
and Th2 cells almost 20 years ago, they are
not the only effector cells with ties to the IL17 family. IL-25 (or IL-17E) has links to the
Th2 lineage, and other IL-17 family members
can be produced by CD8 T cells, γδ T cells,
or natural killer (NK) cells, and by granulo-
822
Weaver et al.
cytes. Members of the IL-17 family are central players in various arms of the adaptive
immune response and have become key to an
expanded understanding of cytokine networks
that coordinate innate and adaptive immunity
to certain pathogens. IL-17 cytokines are also
key mediators in a diverse range of autoinflammatory disorders. The identification of
Th17 cells as the principal pathogenic effectors in several types of autoimmunity previously thought to be Th1-mediated promises
new approaches for therapies of these disorders, as does identification of IL-25 as a potentially important mediator of dysregulated
Th2 responses that cause asthma and other
allergic disorders. Although our understanding of the links between members of the IL-17
cytokine family and adaptive immunity is relatively new, many features of the landscape and
logic of its contribution to innate and adaptive
immunity, whether protective or pathogenic,
are now in place and are the subject of this
review.
PRINCIPLES OF EFFECTOR
T CELL HETEROGENEITY
AND DEVELOPMENT LINKING
INNATE AND ADAPTIVE
IMMUNITY: THE Th1-Th2
PARADIGM
CD4 T cells play a central role in orchestrating immune responses through their capacity to provide help to other cells of the
adaptive or innate immune systems. In early
studies of CD4 T cell biology, it became
apparent that two classes of CD4 T cells
could be defined: those that helped B cells
for class switching, or promoted humoral immunity, and those that enhanced macrophage
activation, or promoted cell-mediated immunity. With the advent of techniques for
cloning T cells (2), investigators found that
these activities typically resided in distinct
cloned populations (3) and correlated with
differential production of factors that promoted or inhibited B cell class switching
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to IgE (4), indicating interclonal functional
heterogeneity of CD4 T cells. The activities responsible for these disparate functions
were identified as T cell–derived cytokines,
initially defined using specific bioassays, and
subsequently using cloned cytokines and specific neutralizing antibodies. On the basis of
these findings, Mosmann & Coffman (5) proposed the T helper type 1 (Th1)-Th2 hypothesis, which postulated that subsets of CD4
T cells produce reciprocal patterns of immunity through their production of distinct profiles of cytokine secretion—either delayedtype hypersensitivity/cell-mediated immunity
(Th1) or allergic/humoral immunity (Th2).
Furthermore, each subset promotes its own
development and inhibits the development
of the other subset, also via their secreted
cytokines (6, 7), such that the induction of
one type of response suppresses the induction of the other (8). This hypothesis established a new paradigm for understanding immune regulation by CD4 T cells and led to
the appreciation that effector CD4 T cells,
like class-switched B cells, are functionally
heterogeneous.
Th1 cells were defined on the basis of
their production of interferon (IFN)-γ, a potent macrophage-activating cytokine important in the clearance of certain intracellular
pathogens and a switch factor for induction of IgG2a production by B cells. Th2
cells became defined as producers of IL4 and IL-5, which promote IgG1 and IgE
class switching and eosinophil recruitment.
Th2 cells were later shown also to produce
IL-13, which participates in IgE class switching and is important for mucosal activation
(mucus hypersecretion and increased contractility). Accordingly, the cytokines produced
by Th2 cells also became identified as factors involved in the clearance of helminthes
(reviewed in 9). The importance of an appropriate Th1 or Th2 response was demonstrated in early studies that examined host
protection to challenge by the obligate intracellular protozoal parasite, Leishmania major,
by genetically resistant and susceptible strains
(10). Protection of a resistant mouse strain,
C57Bl/6, correlated with an appropriate Th1mediated IFN-γ response, whereas susceptibility of BALB/c mice correlated with an
inappropriate Th2-mediated IL-4 response
(11). Susceptible BALB/c mice could be protected by transfer of a Th1 cell line specific to an immunodominant L. major antigen,
whereas transfer of a Th2 cell line exacerbated disease (12). Thus, the Th1-Th2 hypothesis explained the divergence of distinct
types of immunity—types 1 and 2, induction
of which could determine success or failure
of host protection, depending on the type of
pathogen.
It was soon established that Th1 and
Th2 cells, i.e., effector T cells, were rare in
the normal T cell repertoire and required
antigen-driven differentiation or clonal expansion of naive T cell precursors for development. However, it was uncertain whether
both effector cell types could be generated
from clonal precursors of the same antigenic
specificity or whether different antigens were
somehow linked to the preferential induction
or selection of a type 1 or 2 response. With
the advent of T cell receptor (TCR) transgenic models, which provided a large source
of naive T cell precursors of identical antigenic specificity, definitive studies on the development of Th1 and Th2 cells became possible. Th2 development was soon proven to
depend on IL-4, providing the first indication
of a positive feedback loop whereby a cytokine
produced by effector T cells could induce the
differentiation of additional effectors of the
same phenotype (13, 14). Thus, Th2 cells may
beget Th2 cells, through an IL-4-dependent
mechanism.
Discovery of the factors that induce
Th1 development followed from studies
that directly examined the effects of a
Th1-associated pathogen, Listeria monocytogenes, on the differentiation of naive CD4
T cells. Murphy and coworkers (15) found
that macrophages activated by heat-killed L.
monocytogenes induced strongly polarized Th1
responses and that this effect could be blocked
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Janus kinases
(JAKs): a family of
four
signal-transducing
tyrosine kinases
(JAK1, JAK2, JAK3,
and TYK2) that is
associated with the
intracellular domains
of a number of
cytokine receptors.
JAKs are activated by
ligand binding,
resulting in the
phosphorylation and
activation of STAT
homodimers
Signal transducers
and activators of
transcription
(STATs): a family of
seven structurally
related proteins
(STAT1, 2, 3, 4, 5a,
5b, and 6) that are
latent cytoplasmic
transcription factors
acted upon
downstream of
activated cytokine
receptors by JAK
kinases
824
9:49
by neutralization of IFN-γ, although IFNγ alone could not induce as robust a Th1
response as that of macrophage-derived factors elicited by heat-killed L. monocytogenes.
This implicated an additional factor acting
in concert with IFN-γ to induce Th1 differentiation. IL-12, a heterodimeric cytokine
that had been defined as a potent inducer
of IFN-γ production by NK cells (16), was
soon identified as the Th1-inducing cofactor responsible for Th1 development (17, 18).
This provided a mechanism linking pathogendriven innate immune activation to a directed
adaptive T cell response and introduced a
new cytokine pathway involved in coordination of innate and adaptive immune responses.
Thus, cytokine signals induced by firstline innate responses could guide the adaptive response to enhance pathogen clearance
(19).
Following establishment of the cytokines
that polarize Th1 or Th2 differentiation, delineation of key signaling pathways followed
(Figure 1) (see 20 for review). Notably, each
of the Th1- or Th2-polarizing cytokines are
members of the type I cytokine superfamily,
receptors for which are heterodimers that signal via JAK/STAT complexes (21). Th1 differentiation is initiated by coordinate signaling through the TCR and STAT1-associated
cytokine receptors (Figure 1a). Both type I
and type II IFNs activate STAT1, as can the
IL-12 family member IL-27, receptors for
each of which are expressed on naive T cells
(22–24). STAT1 signaling induces the transcription factor, T-bet (Tbx-21), which is a
master regulator of Th1 differentiation (25,
26). T-bet potentiates expression of the Ifng
gene and upregulates the inducible chain of
the IL-12 receptor (IL-12Rβ2), expression
of which enables IL-12 signaling through
STAT4. Activation of the IL-12 receptor further potentiates IFN-γ production and induces expression of IL-18Rα, thereby conferring responsiveness to IL-18 by mature
Th1 cells. The IL-12-driven component of
Th1 development, which is downstream of
STAT1-induced early differentiation, results
Weaver et al.
in mature effector cells that can produce
IFN-γ through either TCR-dependent or
-independent (IL-12 plus IL-18) pathways
(27, 28). Thus, IL-12, elicited from innate
immune cells activated by pathogen recognition, may affect Th1 development through
multiple mechanisms; it can act early, by recruiting IFN-γ production from NK cells,
and late, by driving STAT4-dependent IFNγ production in concert with TCR or IL-18
signaling.
Th2 differentiation is initiated by TCR
signaling in concert with IL-4 receptor signaling via STAT6 (Figure 1b). Signals that
emanate from the TCR and IL-4 receptors act
cooperatively to upregulate low-level expression of GATA3, master regulator of Th2 differentiation (29–31). GATA3 autoactivates its
own expression and drives epigenetic changes
that enable expression of the Th2 cytokine
cluster (Il4, Il5, and Il13 genes), while suppressing factors critical to the Th1 pathway,
such as STAT4 and the IL-12Rβ2 chain (32–
34). Thus, early IL-4 signaling rapidly initiates positive and negative feedback loops
that serve to reinforce early commitment to
Th2 development while extinguishing Th1
development.
The cellular sources of the polarizing cytokines responsible for Th1 and Th2 development in vivo have been the subject of considerable debate. Although Th1 and Th2 cells
can themselves provide IFN-γ or IL-4 for
the recruitment of Th1 or Th2 differentiation, respectively, investigators have not yet
definitively determined which cells initiate effector T cell differentiation in primary versus
secondary responses. Plasmacytoid dendritic
cells (DCs), NK cells, or NKT cells appear to
be involved in early production of type I and
II IFNs for induction of Th1 cells, but which
cells initiate Th2 development is less clear.
Basophils, eosinophils, mast cells, and NKT
cells are sources of IL-4 that may be important for Th2 differentiation (35–39), and each
of these cell populations may be important for
initiating Th2 responses to distinct pathogens
or in distinct settings.
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a
NK
Type 1 pathogens
(Bacteria, viruses)
IL-12
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IFN-γγ
STAT1
mDC1
Antigen, IL-12 + IL-18
IFN- γ
IL-18Rα
IL-12Rβ2
IFN-γ
Th1
LTα
STAT4
T-bet
IL-12Rβ1/β2
IL-12Rβ1
b
IL-18R
IL-12R
IL-12
Type 2 pathogens
(Helminthes)
IL-12Rβ1
IL-12Rβ1
IL-4
GATA3
mDC2
IL-12Rβ2
Th2
c-Maf
GATA3
STAT6
IL-4
Antigen
Basophil Eosinophil
NKT
c-kit+
IL-5
IL-25
Figure 1
Models for (a) Th1 and (b) Th2 differentiation. See text, and references therein, for details.
www.annualreviews.org • The Expanding Diversity of Effector T Cell Lineages
825
IL-4
IL-5
IL-13
IL-25
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THE IL-17 CYTOKINE FAMILY
Toll-like receptors
(TLRs): a primitive
family of at least
11 germline-encoded
pattern recognition
receptors that
recognize immutable
pathogen-associated
molecular patterns
(PAMPs) to induce
innate immune cell
activation
826
Discovery, Family Relationships,
and Origins
Recent discovery of the IL-17 cytokine family has provided a new pathway for crosstalk
between, and coordination of, adaptive and
innate immunity. The family now includes six
members (Table 1), at least three of which are
produced by T cells and have potent proinflammatory properties. A cDNA encoding
IL-17 was isolated from a murine cytotoxic
T lymphocyte (CTL) hybridoma cDNA library in a screen to identify inducible CTLassociated transcripts, and was originally
called CTLA-8 (cytotoxic T lymphocyteassociated-8) (39a). Subsequently, the homologous T lymphotrophic herpesvirus Saimiri
gene 13 was cloned and used to isolate a cDNA
encoding a receptor that bound CTLA-8
(40). The mammalian and viral homologs
were renamed IL-17 and vIL-17, respectively,
and the receptor was named IL-17R. Five
homologous cytokines were later identified
through database searches and degenerative
PCR strategies (see 41 for review). IL-17 has
been designated IL-17A to indicate that it is
the founding member of this extended, sixmember cytokine family, which now includes
IL-17A–F. IL-17E was independently identified and named IL-25 (42), a nomenclature
that we use here.
IL-17F has the highest homology with IL17A, as they are 50% identical at the protein
level. IL-17B–D have lower homology, and
IL-25 (IL-17E) is the least related, sharing
only 16% identity at the primary amino acid
sequence in humans. IL-17A and IL-17F are
syntenic, tightly linked in all species examined
to date; the remaining family members each
map to different chromosomes. IL-17 shares
no sequence homology with other known
mammalian proteins and therefore constitutes
a distinct cytokine family.
Recombinatorial systems for generation of
diverse antigenic receptors in lymphocytes
appear at the dawn of vertebrate evolution
and define the emergence of the adaptive imWeaver et al.
mune system approximately 500 mya (43).
The emergence of most cytokines coincided
with vertebrate evolution and, with the exception of IL-1 receptor–related molecules (including TLRs) and TGF-β, they have not
been identified in invertebrates. Homologs of
the IL-17 family have been identified in all
vertebrates examined to date. As with most
other cytokine families, the IL-17 family appears to have arisen prior to the divergence
of teleosts (bony fishes) and tetrapods (landdwelling vertebrates). Five genes with homology to mammalian IL-17 members have been
identified in zebrafish, suggesting that gene
duplications that gave rise to the IL-17 family occurred very early in vertebrate evolution (44). Three of the zebrafish genes show
homology to both IL-17A and IL-17F, and,
although two are linked, they do not show
synteny with human IL-17A or IL-17F. IL17D is the most evolutionarily conserved IL17 family member, with four divergent fish
species sharing significant sequence identity
and synteny with the human and mouse IL17D genes. Interestingly, an IL-17R homolog
has been identified in lamprey, an ancient
jawless fish, suggesting that the IL-17 family
may have been one of the first cytokine families to emerge (45). Because IL-17 expression
can be regulated by TGF-β and IL-1 family
members, both more primitive components
of the innate immune system, IL-17 may have
evolved to bridge innate and adaptive immune
functions. Th2 cytokines (IL-4, IL-5, and IL13) have only been identified in mammals, indicating emergence much later in evolution,
and have recently been identified as targets for
induction by IL-25 (42).
Structure and Function
The crystal structure of a single IL-17 family
member, IL-17F, has been solved (Figure 2)
(46). It reveals that IL-17F is a structural homolog of the cysteine knot family of proteins,
so named for their unusual pattern of intrachain disulfide bonds. A similar structural motif is found in growth factors such as TGF-β,
CX2
IL-27
IL-25
ML-1
IL-17C
IL-17D
IL-17E
IL-17F
CX1 NERF
IL-17 CTLA-8
IL-17A
Il17f
Il25
Il17d
Il17c
Il17b
Il17a
Gene
name
1 A4
14 C2
14 C3
8 E1
18 D3
1 A4
Chromosomal
location
34
38
45
43
41
35
Predicted
molecular weight
(kDa)
45
16
16
24
21
100
%
Homology
with IL-17A
54
76
82
75
88
62
%
Homology
with human
Th17 cells, CD8 T
cells, NK cells, γδ
T cells, neutrophils
Th2 cells,
eosinophils, mast
cells
?
?
?
Th17 cells, CD8
T cells, NK cells,
γδ T cells,
neutrophils
Cellular sources
IL-17RA
IL-17RC
(IL-17RL)
IL-17RB
(IL-17RH1)
(IL-25R)
?
?
IL-17RB
(IL-17RH1)
(IL-25R)
IL-17RA
(IL-17R)
Receptor
(alternative name)
19 February 2007
IL-17B
Alternate
names
Family
member
The mouse IL-17 cytokine family
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Table 1
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Figure 2
Structure of IL-17F. (a) Ribbon diagram of the IL-17F monomer, highlighting sulfur atoms of cysteines
involved in disulfide bonds (yellow balls). The inset shows a representation of the canonical cystine knot
fold. (b) Ribbon diagram of the IL-17F homodimer, with the disulfides (inter- and intrachain)
highlighted as in (a). (c and d ) Orthogonal surface views of the side (c) and front (d ) of the IL-17F
homodimer, with acidic residues indicated in red, basic residues in blue, and neutral residues in white.
The positions of the potential receptor binding cavities are indicated by broken circles. Used with
permission from Reference 46.
nerve growth factor (NGF), bone morphogenetic proteins, and platelet-derived growth
factor-BB, except that in these other growth
factors the cysteine knot is formed with six
cysteines rather than four. The four cysteines that form the cysteine knot structure in
IL-17F are conserved in all IL-17 family
members and across species.
Structural features of IL-17 family members deduced from the crystal structure of
IL-17F suggest that, similar to many cytokines, each of the family members is likely
produced as a homodimer, although structural
similarities do not exclude the possibility that
heterodimers may exist. With the exception of
IL-17B, the homodimers are stabilized by interchain disulfide bridges. IL-17F dimerizes
in a parallel fashion to that of NGF and other
neurotrophins, with each monomer forming a
relatively large, flat interface that is stabilized
by interchain disulfide links. Along the edges
of contact faces of the IL-17F homodimer
are two large cavities positioned similarly to
sites where NGF binds its high-affinity recep828
Weaver et al.
tor, TrkA, suggesting parallels between IL-17
family members and neurotrophins with respect to receptor recognition. Interestingly,
modeling of other IL-17 family members on
the basis of the IL-17F structure suggests that
this surface feature is conserved, with the lateral cavities lined by variable residues that
may confer receptor binding specificity. By
extrapolation to the binding of NGF with
its high-affinity receptor, researchers propose
that IL-17 family members likely interact with
their cognate receptors through interactions
in these surface cavities (46).
Like the IL-17 cytokine family, the IL-17
receptors form a unique family (reviewed in
47). There are five family members, including
the founding member, IL-17R (or IL-17RA),
and four additional members have been identified through sequence homology searches.
Individual family members share only limited sequence similarity with each other and
do not contain domains found in other proteins; they therefore constitute a novel family of cytokine receptors. All are predicted to
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be single-pass transmembrane proteins with
an extracellular amino terminus and large
intracellular tails. Four of the IL-17 receptor family members map to human chromosome 3 in two tightly linked clusters: IL17RB (also called IL-17RH1 or IL-25R) with
IL-17RD (also called SEF or IL-17RLM),
and IL-17RC (also IL-17RL) with IL-17RE.
There is similar clustering of these pairs
in the mouse. Evidence suggests that, with
the notable exception of IL-17RA, each of
these receptors has an alternative splice variant. Alternative splicing of IL-17RB and IL17RC creates frameshifts and introduces stop
codons that result in secreted soluble proteins (48, 49). Presumably these soluble receptors retain their ligand-binding properties
and act as decoys, although this has not been
demonstrated.
Detailed functional studies of the IL-17
receptor family have not yet been reported.
The best-studied member to date, IL-17RA,
binds both IL-17A and IL-17F, although
IL-17A binds with more than tenfold higher
affinity (46). Expression of IL-17RA appears
to be ubiquitous, hence the broad tissue responsiveness to IL-17A. Mice with targeted
deletion of Il17ra have profound defects in
host protection (50), consistent with a critical
role for IL-17A and IL-17F in host defense.
Of the four remaining family members, only
IL-17RH1 has been shown to bind IL-17
cytokines, namely IL-17B and IL-25 (51, 52);
IL-17RL, IL-17RD, and IL-17RE have only
been identified by sequence similarities to
IL-17R, and their ligand specificities are not
yet reported.
Like all other known cytokine receptors,
IL-17RA appears to be expressed as a multimer, existing as a preformed complex prior
to ligand binding (53). Interestingly, the IL17RA complex undergoes a conformational
change upon binding of IL-17A or IL-17F,
which leads to dissociation of the intracellular
domains. Whether IL-17R family members
can interact with other, nonfamily member
components for signal transduction is unknown, although the cytoplasmic domains do
not appear to contain identifiable catalytic
motifs (40, 54). In this regard, it is notable that
the neurotrophins, with which the IL-17R ligands have structural homology, not only bind
specific Trk receptors, but also bind simultaneously to p75NTR , a common second receptor component. Although not yet proven,
the IL-17 receptors may be multicomponent
signal transducers analogous to neurotrophin
receptors (46). A single report has identified
the participation of a second IL-17R family member, IL-17RC, as a component of a
heteromeric IL-17R that includes IL-17RA
(54a), suggesting greater complexity in the
IL-17R family than previously appreciated.
Relatively little is known regarding signal
cascades generated by ligand binding of IL17 family members. Current studies indicate
that IL-17Rs may signal through MAP kinases or NF-κB, the latter suggesting similarities to the tumor necrosis factor (TNF), IL1, and TLR families. In this regard, IL-17R
signaling is impaired by deficiency of TNFreceptor-associated factor 6 (TRAF-6) (55).
However, there is no identifiable homology
of the IL-17R intracellular domain with those
of the TNF, IL-1, or TLR families. Thus,
neither the intracellular nor extracellular domains of IL-17 receptors resemble other receptors, establishing their unique evolutionary origins and function.
Cellular Sources and Targets
The cellular sources for members of the IL17 family are distinct. IL-17A and IL-17F
were originally associated with memory CD4
T cells and have more recently been specifically linked to the Th17 lineage (reviewed
in 41, 56). However, IL-17A and IL-17F do
not appear to be limited to CD4 effector
T cells. CD8 T cells, γδ T cells, and NK
cells have also been identified as sources of
these two cytokines, as have neutrophils (57–
59; L. Harrington & C. Weaver, unpublished
observations). To date, there are no reports of
discordant expression of IL-17A and IL-17F
by immune cells, consistent with their tightly
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clustered genomic organization and, perhaps,
coordinate regulation during effector T cell
development. These two genes therefore appear to comprise a Th17 gene cluster analogous to the Th2 gene cluster composed of
the Il4, Il5, and Il13 genes. IL-17D may be
expressed by resting CD4 T cells and at low
levels from B cells, although its function is not
yet well defined (60). IL-17B and IL-17C do
not appear to be products of lymphocytes, but
they may be recruited indirectly by IL-17A
and IL-17F and have a number of overlapping activities with these family members (47,
51, 61, 62). IL-25 has been linked to Th2-type
responses and is produced by in vitro–derived
Th2 lines (42), although whether IL-25 is expressed by classical Th2 cells in vivo is unclear
(see below).
Both IL-17A and IL-17F can induce the
expression of diverse proinflammatory cytokines and chemokines from a large variety of cells, as expected from the broad
tissue expression of IL-17RA (reviewed in
41). In the initial characterizations of IL17A, it was found to be a potent inducer of
IL-6 and IL-8 (CXCL8) by fibroblasts (40,
63). Subsequent studies have demonstrated
proinflammatory effects on a broad range
of cellular targets, including epithelial and
endothelial cells, fibroblasts, osteoblasts, and
monocyte/macrophages. Depending on the
target cell population, principal activities of
IL-17A and IL-17F include the induction of
expression of colony-stimulating factors (e.g.,
GM-CSF and G-CSF), CXC chemokines
(e.g., CXCL8, CXCL1, and CXCL10), metalloproteinases, and IL-6. Accordingly, IL17A and IL-17F have potent actions to mobilize, recruit, and activate neutrophils. Indeed,
the capacity of T cell–derived IL-17A and IL17F to expand and recruit the neutrophil pool
is a defining feature of these family members
and provides a novel mechanism by which T
cells coordinate adaptive and innate immunity (see 41, 64 for review). Although there
appears to be considerable overlap in the expression and functions of IL-17A and IL-17F,
there are also likely to be nonredundant fea-
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Weaver et al.
tures; the substantially higher affinity of IL17R for IL-17 over IL-17F suggests that IL17F may preferentially bind a distinct member of the IL-17R family (46). Consistent with
this, mice with a targeted deletion of the Il17a
gene alone have a profound phenotype that
does not appear to be compensated by intact
Il17f expression (65, 66).
Interestingly, some actions of IL-17A and
IL-17F are potentiated by other inflammatory cytokines, particularly TNF-α and IL1β. In this regard, it is notable that IL-17B
and IL-17C are potent activators of TNF-α
and IL-1β expression by certain macrophage
populations that lack IL-17RA, providing a
mechanism for coordinating inflammation by
subsets of the IL-17 family (41).
In contrast to IL-17A and IL-17F, IL25 (IL-17E) induces the expression of CC
chemokines, such as CCL5 (RANTES) and
CCL11 (Eotaxin 1), both of which are important for the recruitment of eosinophils,
as well as the expression of Th2 cytokines,
IL-5, IL-13, and perhaps IL-4 (42, 67). Recent studies have identified a novel innate
immune cell population that is a target for
IL-25 actions (discussed below), hence the
involvement in Th2-type allergic responses.
Therefore, distinct IL-17 family members
are potent orchestrators of innate immunity
mediated by polymorphonuclear leukocytes;
IL-17A and IL-17F recruit neutrophilic responses, whereas IL-25 recruits eosinophilic
and basophilic responses.
THE Th17 LINEAGE: A NEW
ARM OF ADAPTIVE IMMUNITY
Crosstalk Between the IL-17 and
IL-12 Cytokine Families: New
Lessons from Models of Infection
and Autoimmunity
In a reprise of sorts of the seminal report that
linked Th1 polarization to APC activation by
the intracellular pathogen, L. monocytogenes
(15), Kamradt and colleagues (68) examined
the effects of the causative agent of Lyme
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disease, the spirochete Borrelia burgdorferi, on
the in vitro development of effector CD4 T
cells. Compared with controls differentiated
under classic Th1-polarizing conditions by
addition of IL-12, the gene expression profile of T cells differentiated in the presence
of B. burgdorferi sonicates or B. burgdorferi–
derived lipopeptides was distinct and included
increased levels of IL-17A mRNA. Importantly, single-cell analyses identified a fraction
of effector T cells positive for IL-17A, GMCSF, and TNF-α and negative for IFN-γ or
IL-4, revealing a novel cytokine phenotype
distinct from Th1 or Th2. This report not
only established the first link between bacterial infection and a new effector T cell phenotype later to become Th17, but it also presaged description of a factor later identified as
critical to Th17 development: IL-6.
Concurrent with these findings, Kastelein
and colleagues (69, 70) reported the discovery of the first new member of what was to
become the five-member IL-12 family (see
also Reference 131 in this volume). IL-12, the
family prototype, is composed of IL-12p40
and IL-12p35 subunits that form a disulfidelinked heterodimer required for function. On
the basis of greater susceptibilities to infection
of mice deficient for the IL-12p40 (Il12b−/− ),
compared with those deficient for IL-12p35
(Il12a−/− ), investigators speculated that IL12p40 might form functional complexes with
other partners (70). In a database search for
sequences homologous to IL-12p35, a novel
protein was identified (IL-23p19) that could
pair with IL-12p40 to form a distinct, heterodimeric cytokine that was named IL-23
(Figure 3). Soon after, Aggarwal et al. (71) reported that IL-23, but not IL-12, stimulated
memory, but not naive, CD4 T cells to produce IL-17A and IL-17F, a pivotal finding that
linked the IL-17 and IL-12 families and that
was consistent with a unique effector CD4 T
cell population similar to that previously reported by Kamradt and colleagues (68).
Definitive evidence identifying an IL-23dependent pathway for IL-17-producing T
cells came from studies of immune patho-
genesis in murine models of autoimmunity.
Experimental autoimmune encephalomyelitis
(EAE) and collagen-induced arthritis (CIA)
had been associated with aberrant Th1 responses, in part on the basis of studies demonstrating that disease development was blocked
in mice deficient in the p40 subunit of IL-12
(Il12p40 or Il12b) or in mice treated with
IL-12p40-specific neutralizing antibodies
(72–74). However, there were also data from
a number of studies that were inconsistent
with a simple Th1 or IL-12-IFN-γ cytokine
axis link in EAE and CIA: Mice deficient in
IFN-γ were susceptible to both diseases, as
were mice deficient in proximal components
of IFN-γ signaling pathway (Ifngr−/− and
Stat1−/− ) (75–80).
Cua and coworkers (81, 82) provided a
resolution of this paradox when they revisited the immunopathologic basis for EAE and
CIA using mice deficient in either IL-12 or
IL-23, or both. They found that disease development was ablated in mice deficient in
IL-23 or both IL-23 and IL-12, but not in
mice deficient in IL-12 only. Mice deficient in
the IL-23p19 subunit (Il23a−/− , lacking IL23 only) or the IL-12p40 subunit (Il12b−/− ,
lacking both IL-23 and IL-12) were resistant
to EAE and CIA, whereas IL-12p35-deficient
mice (Il12a−/− , lacking IL-12 only) remained
susceptible. These findings were consistent
with another study that found that mice lacking the IL-12 receptor complex (Il12rb2−/− )
also succumbed to EAE (83). Thus, IL-23, not
IL-12, is critically linked to autoimmunity in
these models.
Consistent with the previous identification of induction of IL-17A by IL-23 (71)
was the finding that mice deficient in IL-23
lost development of a population of an IL17-expressing subset of CD4 T cells, while
retaining IFN-γ-producing, Th1-type cells.
A reciprocal pattern of IFN-γ- and IL-17Apositive cells was found in IL-12p35-deficient
mice that developed exacerbated disease compared with wild-type controls (82). A positive correlation was established between IL23, IL-17-producing effector T cells, and
www.annualreviews.org • The Expanding Diversity of Effector T Cell Lineages
Experimental
autoimmune
encephalomyelitis
(EAE): a rodent
model of multiple
sclerosis induced by
immunization with
antigenic
components of
myelin, leading to a
T cell–dependent
central nervous
system inflammation
resulting in focal
demyelination
Collagen-induced
arthritis (CIA): a T
cell– and
antibody-mediated
rodent model of
autoimmune arthritis
in which chronic
joint inflammation is
induced by
immunization with
collagen proteins;
models many aspects
of rheumatoid
arthritis
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TGF- β
IL-6
IL-23
IL-27
Latent
p40
Active
EBI3
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p19
TGF-βR
TGF-βR
gp130
Smad2/3/4
Ser/Thr kinase domain
IL-6Rα
IL-12Rβ1 IL-23R
STAT3
STAT1
STAT3
STAT4
p28
gp130 IL-27Rα
STAT1
STAT3
Immunoglobulin domain
Kinase domain inhibitor
Cytokine receptor homology domain
Fibronectin-like domain
Figure 3
Cytokine pathways involved in Th17 development. Shown are the key cytokines and receptor pathways
by which Th17 lineage commitment is induced, or in the case of IL-27, suppressed. Structural homology
between the IL-6, IL-23, and IL-27 receptors is evident, including the shared component of the IL-6 and
IL-27 receptors, gp130. The TGF-β, IL-6, and IL-27 receptors are expressed by naive T cells, as is the
IL-12Rβ1 chain that is common to the IL-12 and IL-23 receptors. The inducible chain of the IL-23
receptor, IL-23R, is expressed downstream of Th17 lineage commitment. The TGF-β receptor
phosphorylates the receptor-regulated Smads (RSmads) 2 and 3 upon binding of activated ligand that has
been released from latency-associated peptide components, permitting recruitment of the co-Smad,
Smad4 and nuclear translocation (see References 129 and 130 for reviews). The mechanisms by which
active TGF-β is generated for T cell differentiation are unknown. Activation of the principal STATs
thought to be important in Th17 differentiation is indicated in black; other STATs recruited by these
receptors are indicated in gray, but their function in Th17 biology is unclear.
disease development, and a negative correlation between IL-12, IFN-γ-producing Th1
cells, and disease development. In accord with
these findings, impaired joint inflammation
was reported in IL-17A-deficient mice following type II collagen immunization (66), and
neutralization of IL-17A also decreased disease severity (84–86). Furthermore, overexpression of IL-17 in the joints exacerbates disease (85, 87). Collectively, these data strongly
832
Weaver et al.
implicated a role for the IL-23-induced development of IL-17-producing effector T cells
in autoimmune inflammation; the production
of classical Th1 cells was insufficient for disease development and, in some settings, exacerbated disease.
Further data linking IL-17-producing effectors and immune pathogenesis came with
studies in which IL-17-producing CD4 T
cells primed for reactivity to the CNS
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antigen proteolipid protein peptide, and enriched by culture with IL-23, induced severe EAE in recipient mice following passive
transfers, whereas Th1 cells enriched by culture with IL-12 did not (88). This study further defined functional and phenotypic differences of so-called ThIL-17 cells and Th1 cells,
demonstrating that gene expression profiles of
these two subsets were quite distinct. Thus,
whereas IL-12-polarized cells, i.e., prototypic Th1 cells, preferentially expressed genes
associated with cytotoxicity (IFN-γ, FasL,
and granzymes), IL-23-polarized cells expressed genes associated with chronic inflammation (IL-17/IL-17A, IL-17F, IL-6, TNFα, and proinflammatory chemokines). These
results confirmed a new role for IL-17producing effectors cells (later termed Th17)
in immunopathogenesis and strongly suggested that Th1 and Th17 cells represent
distinct effector subsets that develop under
differential conditions of IL-12 or IL-23
conditioning.
Administration of neutralizing antibody
specific for IL-23 proved an effective therapy for both inhibiting and treating EAE (89).
Treatment with anti-IFN-γ resulted in significant worsening of clinical disease, associated with elevated levels of serum IL-17A and
consistent with an antagonistic role for IFN-γ
in Th17-mediated CNS inflammation. Treatment with anti-IL-17A had a significant, but
modest, effect on amelioration of CNS inflammation and clinical disease score compared with treatment with anti-IL-23, in line
with previous studies showing only partial remediation by blockade of IL-17. Whether
this is due to compensatory effects of IL-17F,
which is also produced by Th17 cells, IL-17independent effects of IL-23, or both remains
to be determined.
Th17: An Effector Lineage Distinct
from Th1 and Th2
On the basis of these findings, investigators proposed two alternative models for differentiation of Th17 cells (64, 90). In one
model, the early differentiation of Th1 and
Th17 from naive CD4 T cell precursors
was shared, such that IFN-γ- and IL-17expressing subsets diverged contingent upon
selective availability of IL-12 and IL-23 acting on a common Th1-precursor or pre-Th1
intermediate that coexpressed both IL-12 and
IL-23 receptors. In the other model, the development of IFN-γ and IL-17 producers was
nonoverlapping and represented distinct lineages. Because T-bet and STAT4 are required
for disease development in EAE and CIA,
whereas IL-12, IFN-γ, and STAT1 are not,
a corollary of the latter model predicts that
T-bet and STAT4 contribute to disease development through Th17-independent mechanisms, or perhaps have critical roles in both
lineages.
In a pair of reports, one from our group and
the other from Dong and colleagues (91, 92),
direct support for a Th1-independent pathway of Th17 differentiation was established
(Figure 4). We found that IL-23 failed to induce IL-17 production from Th1-polarized
cells, indicating that Th1 cells are not IL23-responsive. Furthermore, both type II
and type I IFNs, which activate STAT1induced expression of T-bet and Th1 commitment, strongly inhibited Th17 development
in vitro. Together, these findings indicated
not only that the Th1 pathway is nonpermissive to Th17 development, but also that its
defining cytokine, IFN-γ, actively suppresses
Th17 development. Parallel findings were
made for the Th2 lineage; Th2-polarized
cells were unresponsive to IL-23, and IL4 potently inhibited Th17 development. Indeed, neutralization of IFN-γ and IL-4—
whether by blocking antibodies or genetic
deficiency—was required to induce appreciable IL-17-producing effectors under the conditions examined. Key signaling components
of Th1 and Th2 differentiation—STAT1,
T-bet, STAT4, and STAT6—were dispensable for Th17 development. These findings
were extended in vivo by Park et al. (92),
who showed that Th17 development was
unimpaired in immunized mice deficient for
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Foxp3
Treg
TGF-β
IL-10
Smads
TGF-β
β
Antigen, IL-23 + IL-1/18
IL-6
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mDC
Smads
STAT3
IL-17A/F
IL-23R
Th17
STAT3
RORγ t
IL-12Rβ1
Type 17 pathogens
(Bacteria, fungi)
IL-12Rβ1/
IL-23R
IL-23R
IL-17A
IL-17F
IL-6
G-CSF
IL-18R
IL-23
Neutrophil G-CSF
Figure 4
Model for divergent differentiation of Th17 and adaptive regulatory T cell (Treg) lineages. This model
emphasizes distinct pathways leading to mature Th17 effector cells or Foxp3+ adaptive Tregs, contingent
upon a common requirement for TGF-β but differential effects of IL-6 and IL-23. Naive CD4 T cells
activated by antigens presented on an immature dendritic cell (iDC) are induced by TGF-β to express
Foxp3 and develop into Tregs (top). Naive CD4 T cells activated by a mature dendritic cell (mDC)
produce IL-6, which acts in concert with activated TGF-β to induce expression of the retinoic orphan
receptor (ROR) γt and upregulate IL-23R, thus becoming competent for IL-17A and IL-17F production
and IL-23 signaling. IL-23 signaling can act synergistically with IL-23 to induce Th17 cytokine
production independently of TCR stimulation. Alternatively, TCR stimulation by antigen can induce
Th17 cytokine production directly, without a requirement for IL-23, IL-1, or IL-18. G-CSF [and
GM-CSF (not shown)] produced by mature Th17 cells acts to stimulate granulopoiesis and mobilization
of neutrophils. Dotted lines indicate possible positive feedback loops by which cytokine products of
Th17 (IL-6) or Treg cells (TGF-β) may reinforce lineage development.
IFN-γ or T-bet. Collectively, these studies established that IL-17-producing effectors develop via a lineage that is distinct
from, and antagonized by, the Th1 and Th2
lineages.
These findings offer explanations for a
number of the paradoxical effects observed in
the development of EAE and CIA in mice with
Th1-lineage defects. Given the pathogenic
potential of Th17 cells and the suppressive effects of IFN-γ on Th17 development, a mechanism now exists to explain why mice with
834
Weaver et al.
targeted deletions of IFN-γ, IFN-γR, IL-12,
or STAT1 display exacerbated disease development. On the contrary, the disease resistance of mice with genetic or siRNA-induced
T-bet deficiency does not appear to be due to
a defect in Th17 development (92, 93), implicating T cell–independent mechanisms by
which T-bet contributes to pathology. Thus,
T-bet may have complex roles in the Th17
inflammatory cascade outside of the T cell
compartment. In a similar vein, why STAT4deficient mice are also resistant to EAE (94),
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despite an absence of requirement for STAT4
in commitment to Th17 development, is unclear. Because, at least in vitro, STAT4 is dispensable for Th17 development, it remains
to be determined whether the disease resistance of STAT4-deficient mice is due to a
role for this factor in Th17 function or survival, amplification of Th17 cytokine production via IL-23, or a Th17-independent
mechanism.
Th17 Differentiation: A New Role
for Old Cytokines
Despite the clear role for IL-23 in Th17mediated immunopathology and host protection, three independent studies found
that IL-23 is not required for Th17 commitment (95–97). In each study, development of IL-17A/IL-17F-producing effectors
was undiminished under conditions of IL-23
deficiency, and Th17 development was not
enhanced by addition of exogenous IL-23.
Furthermore, differential upregulation of IL12Rβ2 and IL-23R was associated with signals
that induced Th1 and Th17 differentiation,
respectively (91). Thus, as in Th1 development, Th17 development is initiated independently of a requirement for signaling by an IL12 family member; in analogous fashion to the
induced expression of the variable component
of the IL-12 receptor, IL-12Rβ2, the variable
component of the IL-23 receptor, IL-23R, is
upregulated downstream of signals that initiate Th17 differentiation, thereby conferring IL-23 responsiveness. IL-23 signaling is
therefore not required for Th17 commitment
and early IL-17 production, but instead appears to be important for amplifying and/or
stabilizing the Th17 phenotype, a basis for
the finding that IL-23 augments IL-17 production from memory, but not naive, CD4 T
cells (71).
In efforts to define IL-23-independent factors that initiated Th17 cell development, investigators found that TGF-β and IL-6 act
cooperatively and nonredundantly to achieve
Th17 commitment (95–97) (Figures 3 and
4). Stockinger and coworkers (95) showed
that naive T cells activated in the presence of
CD4+ CD25+ regulatory T cells (Tregs) exhibited suppressed levels of IFN-γ and IL-2
production but expressed high levels of IL17A. Antibody blockade of TGF-β in cultures containing LPS-activated DCs, Tregs,
and naive CD4 T cells activated with antiCD3 identified TGF-β as a critical factor
for Th17 development. Importantly, in addition to TGF-β, differentiation of IL-17producing effector cells required a soluble
DC factor elicited by TLR- and MyD88dependent signaling, which proved to be IL6. TNF-α and IL-1β could amplify the frequency of IL-17-producing effectors, but they
were nonessential cofactors. Analysis of transcription factor expression by these Th17
cells showed that compared with Th1 and
Th2 cells, Th17 effectors lacked expression
of T-bet, HLX, and GATA3, supporting and
extending previous findings identifying the
Th17 cell as a product of an effector lineage
distinct from Th1 and Th2 (91, 92).
Our group, and Kuchroo and coworkers,
independently identified TGF-β as a critical
factor for Th17 commitment and showed further that IL-6 acted to deviate TGF-β-driven
development of Foxp3-expressing Tregs toward Th17 (96, 97). Thus, the addition of
IL-6 suppressed the TGF-β-induced generation of Foxp3+ Tregs, while reciprocally
promoting the generation of Th17 cells (reviewed in 56). TGF-β addition under conditions of endogenous IL-6 production resulted
in upregulation of the IL-23R component of
the IL-23 receptor, in contrast to the effects
of IFN-γ, which upregulated the IL-12Rβ2
component of the IL-12 receptor, but not IL23R. More recent studies indicate that high
levels of IL-6 can induce IL-23R independently of TGF-β (P. Mangan & C. Weaver,
unpublished observations). Accordingly, the
antagonistic effects of TGF-β/IL-6 versus
IFN-γ signaling early in the activation of
naive T cells deviate lineage development toward Th17 or Th1, with concomitant upregulation of the inducible components of the
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IL-23 or IL-12 receptor components, respectively. To extend these findings in vivo, we
explored TGF-β1-deficient mice (96). Mice
homozygous for TGF-β1 deficiency were essentially devoid of Th17 cells, which are normally enriched in the lamina propria of the
intestine and in mesenteric lymph nodes (59;
P. Mangan & C. Weaver, unpublished observations). Mice hemizygous for TGF-β1 deficiency showed an intermediate phenotype
compared with controls, and circulating levels of IL-17 correlated with these phenotypes.
Bettelli et al. (97) showed that transgenic
expression of TGF-β under control of the
IL-2 promoter enhanced Th17 development
and exacerbated EAE, whereas IL-6 deficiency inhibited Th17 development. Complementary studies by Stockinger and coworkers (97a) found that deficiency of TGF-β
signaling specific to T cells blocked EAE
development, consistent with the in vitro
observations.
Collectively, these studies support a model
in which TGF-β plus IL-6, IFN-γ, or IL4 initiate commitment to the Th17, Th1, or
Th2 lineages, respectively (Figures 1 and 4).
The requirement for TGF-β in Th17 differentiation is shared with adaptive Tregs, which
default to Foxp3 induction in the absence
of IL-6. Thus, IL-6, elicited by pathogeninduced activation of innate immune cells
via TLRs, is a critical switch factor that
diverts antigen-activated naive T cells toward a proinflammatory rather than antiinflammatory adaptive response (98, 99; reviewed in 56). The dichotomous actions of
TGF-β on Th17 versus Treg development
extend and reinforce previous studies indicating that TGF-β actions are contextual (reviewed in 100) and provide a new framework
in which to view TGF-β actions in adaptive
immunity.
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What Role for IL-23?
The foregoing studies identified critical roles
for TGF-β and IL-6 as proximal factors essential for induction of Th17 development
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Weaver et al.
and established that IL-23 functioned subsequent to Th17 commitment, contingent upon
upregulation of the inducible component of
the IL-23 receptor, IL-23R. Given the critical requirement for IL-23 in Th17 function
in vivo, IL-23 appears to be essential to expand and maintain committed Th17 effectors
and/or extend their function. In this regard,
it is noteworthy that IL-12 acts in Th1 lineage development not only to amplify IFNγ production by Th1-committed precursors
that have upregulated the inducible chain of
the IL-12 receptor, but also to induce upregulation of the IL-18Rα chain, thereby inducing
a TCR-independent pathway to IFN-γ production via the coordinated signaling of IL-12
and IL-18 (Figure 1a). A similar pathway is
now apparent for the Th17 lineage.
IL-18 is a member of the IL-1 superfamily of proinflammatory cytokines that is produced by cells of the innate immune system
(e.g., DCs) and signals through the IL-18 receptor (IL-18R), a heterodimer consisting of
the ligand-binding subunit (IL-18Rα) and a
signaling subunit (IL-18Rβ; also known as
IL-1R7 or IL-1RAcPL) (101, 102). Signaling through the IL-18R has parallels with
the IL-1 and TLRs via activation of MyD88
and IRAK4. IL-18Rα upregulation on Th1
cells is IL-12- and STAT4-dependent (27,
103–105). In view of initial reports of STAT4
activation by IL-23 (70), we recently explored
the possibility that Th17 cells, like Th1 cells,
might use IL-23-induced IL-18 signaling to
amplify IL-17 production. We found that
Th17 cells polarized by TGF-β and IL-6 in
the absence of IL-23 produce IL-17 when
stimulated by IL-23 plus IL-18 or IL-23 plus
IL-1β, but were poorly responsive to IL-23
alone (Y. Lee & C.T. Weaver, unpublished
observation). Thus, Th17 cells appear to parallel Th1 cells with respect to development
of a TCR-independent mechanism for cytokine production (Figure 4). Furthermore,
Th17 commitment induced by TGF-β and
IL-6 may prime developing Th17 cells for IL23 responsiveness, but IL-23 may be essential for further differentiation of Th17 cells
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that is required for their optimal production
of IL-17A and IL-17F at inflammatory sites.
Accordingly, we found that IL-23 deficiency
did not prevent the development of comparable numbers of IL-17-competent CD4 T
cells in vivo in response to challenge with the
intestinal pathogen, Citrobacter rodentium, although host protection was ablated (56, 96).
Thus, IL-23 has nonredundant functions in
host protection and autoimmunity that are independent of Th17 induction.
Remarkably, Th17 cells may depend on
a novel ligand to activate IL-18R for IL17A/IL-17F production in vivo. In a study
that examined the IL-18 pathway in EAE,
Gutcher et al. (106) found that IL-18deficient mice were fully susceptible to disease, whereas IL-18Rα-deficient mice were
resistant and characterized by a deficient
Th17 response. Disease development in
Il18−/− mice was attenuated using blocking
antibodies to IL-18Rα, implicating an alternative IL-18Rα ligand that drives Th17dependent immunopathology in this model.
Although these data are in conflict with other
studies that indicate protection in IL-18deficient mice (107), they nevertheless suggest that an alternative IL-18R ligand exists
and may be important for Th17 development
or maintenance. Thus, the IL-18 signaling
cascade appears to be important in Th17mediated immunopathology, through binding
of an as yet unidentified ligand distinct from
IL-18. Interestingly, IL-18Rα-expression on
APCs, not T cells, appeared to be necessary
for disease development, implicating a more
complex cytokine network for the IL-18R
pathway in Th17-mediated disease pathogenesis than previously appreciated. Another
study reported that mice deficient for IL-1 receptor type 1 are resistant to IL-1-induced IL17 production and are resistant to EAE (108).
Thus, both IL-1- and IL-18-associated pathways appear important for Th17 function, although additional studies are needed to clarify
their respective roles.
Although the principal focus on IL-23
function has been the Th17 pathway and thus
adaptive immune induction and function, a
report by Powrie’s group (109) identifies an
important role for IL-23 in directly activating
the innate immune system. Using a model
in which systemic administration of the DCactivating antibody, anti-CD40, bypassed the
normal T cell requirement for induction of
murine inflammatory bowel disease (IBD),
these investigators found that many of the
pathologic features of IBD could be demonstrated in RAG-deficient mice and were
therefore T cell– and B cell–independent.
Anti-CD40-induced immunopathology was
effectively inhibited by administration of
anti-IL-12p40 antibody, as well as with neutralizing antibodies to TNF-α and IFN-γ.
Treatment with anti-IL-12- or anti-IL-23specific antibodies revealed distinct roles for
IL-12 and IL-23 in this setting. Neutralization of IL-12 resulted in the reversal of
systemic wasting and inhibition of elevated
serum levels of proinflammatory cytokines
(TNF-α, IL-6, and MCP-1, albeit modestly).
Conversely, neutralization of IL-23 resulted
in dramatic reductions in intestinal expression
of these same cytokines, whereas treatment
with anti-IL-12 had either no effect or, in
the case of IL-6, resulted in exaggerated
levels of expression. Furthermore, treatment
with anti-IL-23, but not anti-IL-12, attenuated intestinal inflammation, supporting
a specific role for IL-23 in local mucosal
inflammation. These results were supported
by gene ablation studies using RAG-deficient
mice crossed into IL-12-, IL-23-, and
IL-12/IL-23-deficient mice. Remarkably,
anti-CD40 administration induced intestinal
expression of IL-17A mRNA independently
of T cells, and this was ablated in IL-12p40and IL-23p19-, but not IL-12p35-deficient
mice. Thus, IL-23 can act on non-T cell
populations to induce expression of IL-17A.
Although the cellular sources responsible for
IL-17 production were not identified, these
data nevertheless provide striking evidence
that the IL-23-IL-17 cytokine axis may play
a central role in intestinal immune pathology
via T cell–independent mechanisms.
www.annualreviews.org • The Expanding Diversity of Effector T Cell Lineages
Inflammatory
bowel disease
(IBD): two chronic
inflammatory
diseases of the
intestines in humans,
ulcerative colitis and
Crohn’s disease, that
are modeled in mice
through
manipulations
resulting in
uncontrolled effector
T cell responses to
the enteric microbial
flora
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Recent studies have extended links with
the IL-23-IL-17 axis to other models of intestinal inflammation (110), identifying a positive correlation with this pathway and IBD
development akin to that identified for EAE
and CIA. Mice deficient in IL-10 develop
a CD4 T cell–dependent, spontaneous colitis within several weeks of birth, depending on strain background (111). Rennick and
colleagues (111) crossed IL-10-deficient mice
with either IL-23-deficient (p19−/− ) or IL-12deficient (Il12p35−/− ) mice and assessed development of colitis. Mice doubly deficient
for IL-10 and IL-12 developed comparable
colitis, whereas mice doubly deficient for IL10 and IL-23 failed to develop disease. On
the basis of these findings, IL-23 was administered to RAG-deficient mice reconstituted
with naive or memory T cells from IL-10deficient mice. IL-23 accelerated the onset
of colitis in both groups and was associated
with elevations of IL-17A and IL-6. Examination of T cell populations from mice doubly deficient in IL-10 and IL-23 showed the
persistence of a small number of IL-17A+
T cells, suggesting that generation of Th17
cells in this setting can occur in the absence
of IL-23, consistent with our own studies indicating that p19-deficient mice developed
IL-17A-competent T cells independently of
IL-23 (96). Administration of anti-IL-6 and
anti-IL-17A, either alone or in combination,
attenuated disease development in mice administered IL-23, indicating that at least part
of IL-23’s effects could be mediated by these
cytokines. Elson at al. (C. Elson, Y. Cong,
C. Weaver, T. Schoeb, T. McClanahan, R.
Fick, and R. Kastelein, manuscript submitted) found that passive transfers of Th17 cells
reactive to the intestinal bacterial flora potently induced IBD compared with transfers
of equivalent numbers of Th1 cells. Treatment of Th17 recipients with anti-IL-23 both
blocked disease development and treated established disease, indicating, again, that even
mature Th17 cells require IL-23 to exercise
their pathogenic effects.
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RORγt: A MASTER REGULATOR
OF Th17 IDENTIFIED
For Th1, Th2, and a subset of Tregs, key
transcription factors have been identified that
can specify most of the genotypic and phenotypic characteristics of these lineages and
have been termed master regulators. Thus,
T-bet specifies Th1, GATA3 specifies Th2,
and Foxp3 specifies Treg development. It had
been speculated that Th17 development may
be similarly linked to its own master. This
now appears to be the case. A new report
by Littman and coworkers (112) has identified the orphan nuclear receptor, retinoic orphan receptor (ROR) γt, as a transcription
factor that appears necessary, and can be sufficient, for Th17 development, providing compelling evidence that Th17 cells develop contingent upon a central transcriptional pathway
that specifies their differentiation. RORγt is
normally expressed in developing thymocytes
(CD4+ CD8+ ) as well as in lymphoid tissue inducer (LTi) cells and LTi-like cells important
for development of cryptopatches and isolated
lymphoid follicles in the lamina propria of
intestinal tissues (113). To examine the role
of RORγt in T cell development and lymphoid organogenesis, Littman and colleagues
generated mice with the coding sequence
for green florescent protein (GFP) knocked
into the initiation site of RORγt translation,
thereby reporting cells activating this locus
while knocking out expression of RORγt from
the targeted allele (114, 115). In a reanalysis
of intestinal cells derived from these mice, a
subpopulation of lymphocytes distinct from
LTi cells and expressing lower GFP levels was
identified. Independent studies that had examined genes differentially expressed by Th1
and Th17 cells identified elevated RORγt
mRNA in Th17, but not Th1, cells, suggesting a link between the RORγt+ T cells in the
intestinal lamina propria and the Th17 lineage. When lamina propria lymphocyte cells
from RORγtGFP/+ mice were isolated and
stimulated, a large fraction of the GFP+ TCR
αβ T cells expressed IL-17 (approximately
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60%), whereas the GFP− fraction did not.
Furthermore, in mice homozygous for the
reporter-targeted allele (and thus RORγtdeficient), the fraction of T cells expressing IL-17 was markedly diminished, though
not completely eliminated. Collectively, these
data established a strong correlation between
expression of RORγt and IL-17A in intestinal effector sites. To investigate the link between RORγt and Th17 development further,
these investigators derived Th17 effectors
in vitro under Th17-polarizing conditions.
Mice deficient for RORγ (which lack both
RORγ and RORγt, products of alternative transcriptional start sites) showed impaired Th17 development in vitro compared
with wild-type controls. Conversely, the induction of Th17 development was correlated with both RORγt expression and IL17 and IL-17F expression. Importantly, the
defect in RORγt-deficient mice was confined to IL-17-producing T cells; differentiation of IFN-γ-producing Th1 cells under Th1-polarizing conditions was normal or
even enhanced compared with wild-type controls. Enforced expression of RORγt in naive
CD4 T cells resulted in IL-17 production
by approximately one-half of cells that expressed RORγt; this was in contrast to cells
transduced with T-bet or empty vector retroviral vectors, neither of which showed significant IL-17 expression. Additional studies correlated the expression of RORγt with
Th17 development and immunopathology in
a model of EAE and demonstrated that IL6-deficient mice showed a correlative loss of
Th17 and RORγt+ intestinal lymphocytes.
Thus, RORγt expression is IL-6- and TGFβ-dependent and is both necessary and sufficient to induce Th17 development by many
CD4 T cells.
Collectively, results from this study establish that RORγt has a role in Th17 differentiation analogous to that for T-bet and GATA3
in the differentiation of Th1 and Th2 cells,
respectively (112) (Figures 1 and 4). Unlike T-bet and GATA3, however, RORγt is
a nuclear receptor whose putative ligand re-
mains unidentified, and it is unknown whether
RORγt activity is regulated by a ligand or
is ligand-dependent. Assuming that the ligand(s) for RORγt must be coordinately expressed to effect RORγt function and, hence,
Th17 specification, this could explain the imperfect correlation found in this study between RORγt expression and IL-17 production, although there are other explanations.
It is also unknown whether RORγt directly
induces IL-17 transcription or acts indirectly
through the induction or suppression of other
factors, although a ROR response element
(RORE) has been identified in an evolutionarily conserved region of the IL-17A promoter,
consistent with a direct role for RORγt in
IL-17 transcription. In any case, linkage of
Th17 differentiation to RORγt represents a
major advance that should accelerate understanding of the signaling circuitry that specifies Th17 programming, including how Smad
and STAT signals emanating from TGF-β
and IL-6 receptors might cooperate to specify
Th17 commitment.
IL-27: A BRAKE ON Th17
DEVELOPMENT?
Much as early characterization of IL-23 identified it as an inducer of Th1 immunity, a third
IL-12 family member, IL-27, has been linked
to Th1 responses, owing in part to its activation of the STAT1 signaling pathway and induction of T-bet (22, 23, 117). However, studies in infectious models have also identified
a role for IL-27 in limiting adaptive immunity, at least in part through its actions on IL2 production (118, 119). More recently, two
studies have redefined the actions of IL-27 by
demonstrating its important role in curbing
Th17 responses by limiting development of
Th17 effectors (120, 121).
Like IL-12 and IL-23, IL-27 is a heterodimeric cytokine and is composed of
Epstein-Barr virus-induced gene 3 (EBI3) and
p28, homologs of IL-12p40 and IL-12p35,
respectively (see 69, 122 for review). IL-27
appears to be produced by similar cells as
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IL-12 and IL-23 (e.g., activated DCs and
macrophages), although few studies have directly addressed the cellular sources of IL27. The receptor for IL-27 is composed of
two subunits, IL-27Rα (also called WSX-1 or
TCCR), expression of which is limited to immune cells, and gp130, which is shared with
several members of the IL-6 receptor family
and is expressed more widely on both immune
and nonimmune cells (123). Unlike the IL12 and IL-23 receptors, which require upregulation of their specific subunits (IL-12Rβ2
and IL-23R) downstream of early activation
events, both components of the IL-27 receptor are expressed by naive T cells; it is
therefore poised for early actions in regulating naive T cell activation and effector T cell
development.
Clues to IL-27’s function in limiting effector T cell responses came initially from
studies of parasitic infections in IL-27Rαdeficient mice (118). Although previous studies indicated that IL-27 could stimulate Th1
development from naive CD4 T cells in vitro,
Hunter and colleagues (118) found that IL27Rα-deficient mice nevertheless generated
robust Th1 responses when challenged with
Toxoplasma gondii and that they succumbed to
an acute, lethal, CD4-dependent inflammatory disease (121). To explore the basis for
this, T. gondii-infected mice were treated to
promote longer-term survival and induction
of more chronic disease. In this setting, IL27Rα-deficient mice showed pronounced inflammatory changes in the CNS that were
not evident in wild-type mice and that were
eliminated by anti-CD4 treatment. When the
CD4 T cells in CNS infiltrates were phenotyped, they were found to express IL-17, IL-6,
and TNF-α, identifying them as Th17 cells
and suggesting that IL-27 signaling might
be required to suppress unchecked Th17
immunity.
Examination of the development of Th17
cells induced by TGF-β and IL-6 in vitro indicated that IL-27 suppressed development of
Th17 effectors (121). In view of the fact that
IL-6 is required for the development of Th17
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cells, and that IL-6 and IL-27 share the receptor component gp130, it was speculated
that IL-27 may act to inhibit Th17 development through competition with IL-6 for receptor binding. Notably, however, even in the
setting of IL-6 neutralization, which substantially blocked Th17 development, the residual IL-17 production was further reduced by
addition of IL-27, indicating that although
competition for gp130 signaling cannot be
absolutely excluded, IL-27 appears to have
additional effects beyond simple competition
for gp130 signaling. The inhibitory effect of
IL-27 was abrogated in naive CD4 T cells
from STAT1-deficient mice, establishing that
suppression of Th17 development by IL-27
is STAT1-dependent, consistent with previous studies demonstrating inhibition by type 1
and type 2 IFNs, which also signal via STAT1
(91). In addition, and consistent with previous reports (91, 92), T-bet-deficient naive
T cells developed into Th17 effectors without compromise, and inhibition by IL-27 was
undiminished in T-bet-deficient precursors,
indicating that activation of T-bet through a
STAT1-dependent mechanism is not required
for the suppressive effects of IL-27 on Th17
development.
Although the precise signaling mechanisms through which IL-6 and TGF-β
cooperate to induce Th17 differentiation
have not been delineated, a central role for
IL-6-induced STAT3 activation is evident.
Like many type 1 cytokines, IL-6 signaling via
STAT3 activates SOCS3 (suppressor of cytokine signaling 3) expression, which provides
a negative feedback mechanism for blocking
cytokine expression, including IL-17 (124).
IL-23 also induces IL-17 via STAT3, and
loss of SOCS3 increases binding of STAT3
to the IL-17 promoter and enhances IL-17
production in response to IL-6 and TGF-β
(124). IL-27 signaling can also induce SOCS3
via STAT1, raising the possibility that IL-27
might block Th17 development (as may type
I and II IFNs) via sequential activation of
STAT1 and SOCS3, resulting in STAT3
antagonism. However, although IL-17
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production induced by TGF-β and IL-6
was modestly increased in Socs3−/− mice,
the suppressive effects of IL-27 were not
greatly diminished (121). Therefore, the
effects of IL-27 to inhibit IL-17 production
are not due to enhanced SOCS3-mediated
dampening of IL-6/gp130. Collectively,
these data indicate that IL-27 acts directly on
naive T cells to suppress the development of
Th17 effectors through a STAT1-dependent,
T-bet-independent mechanism that is not
exclusively mediated by competition for
IL-6/gp130 signaling or suppression of
SOCS3 inhibition of IL-6 signaling.
In an independent report, Ghilardi
and coworkers (120) also identified Th17suppressive effects of IL-27 using an EAE
model and further explored mechanisms
by which IL-27 acts. In agreement with
the findings of Hunter and colleagues
(121), EAE induction was exacerbated in
IL-27Rα-deficient mice and was associated
with increased frequencies of Th17 cells in
the CNS. In vitro, IL-27 suppression was
associated with STAT1-dependent blockade
of upregulation of IL-23R on naive T cells
by IL-6. Therefore, IL-27 and IL-6 act
antagonistically to effect Th17 development,
in part through effects on upregulation of the
inducible component of the IL-23 receptor.
Importantly, IL-27 blocked Th17 differentiation more efficiently than did IFN-γ in vitro,
and suppression via IL-27 or IFN-γ was
not redundant, but additive. Furthermore,
despite the effect of IL-6 on abrogating Tregmediated suppression (98, 99), inhibition of
IL-6-mediated hyperproliferation by IL-27
was independent of IL-6’s actions on Tregs.
Therefore, enhanced proliferation was abrogated only when IL-27Rα was absent from
effector cells, not regulatory cells, and IL-27mediated inhibition of T cell hyperproliferation to IL-6 was blocked even when Treg cells
were removed. Thus, antagonism between
IL-27 and IL-6 occurred via direct actions on
naive T cells, not through actions on Tregs.
These studies are consistent with a mechanism whereby Th17-mediated inflammation
may negatively feed back to limit propagation of Th17 production through actions of
IL-27 production, and they raise important
questions about the conditions under which
IL-27 is produced and by what cells. In the
case of the CNS, where IL-27 may be regulated at the level of p28 expression by astrocytes (121), this may provide a critical mechanism for protection of the brain, which is
highly sensitive to Th17-mediated inflammation. Clearly, additional studies are needed
to define pathways and factors that induce
IL-27, as well as signaling mechanisms by
which IL-27 (and other STAT1-activating cytokines such as the IFNs) act to antagonize IL17 expression. Considering the link between
RORγt expression and Th17 induction (112),
one may speculate that cytokines activating
the STAT1 pathway antagonize induction of
RORγt expression stimulated by cosignaling
through TGF-β and IL-6. In any case, elucidation of the link between IL-27 and Th17
suppression may open new pathways by which
Th17 development can be blunted proximally
rather than after the proinflammatory developmental pathway and cascade have been
established.
IL-25 AND TYPE 2 IMMUNITY
Participation of IL-17 family cytokines in the
Th17 arm of immunity is mirrored by family participation in the Th2 arm. Whereas
IL-17A and IL-17F are Th17 products, IL25 (IL-17E) can be produced by Th2 cells
and now appears to have an important role in
amplifying and/or initiating Th2 responses.
IL-25 was originally discovered via database
search for genes homologous to IL-17 and
other IL-17 family members, and its expression identified in Th2-polarized cells (42).
IL-25 expression was not detected in naive
T cells, Th1-polarized cells, B cells, bone
marrow–derived DCs, macrophages, mast
cells, or endothelial cells, and the in vivo expression of IL-25 mapped to mucosal tissues
almost exclusively. Remarkably, administration of IL-25 to mice recapitulated many of
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the features of type 2 immunity via induced expression of prototypical Th2 cytokines (IL-4,
IL-5, and IL-13): increased serum IgE, IgG1,
and IgA; intestinal and pulmonary epithelial
hyperplasia, goblet cell hypertrophy, and increased mucus production; and eosinophilia
and eosinophilic tissue infiltrates. With the
exception of upregulation of IL-4 and its effects on immunoglobulin subclasses, all other
effects of systemic IL-25 administration could
occur independently of lymphocytes (42, 67).
Thus, IL-25 could induce IL-5 and IL-13 and
their effects on eosinophil recruitment and
mucosal epithelial responses, without requirement for the adaptive immune system.
In an effort to identify the cellular source
of these cytokines, Fort et al. (42) found that
IL-25-responsive cells identified in the spleen
had an unusual phenotype. These cells lacked
classical B and T cell markers, as well as
granulocytes and macrophage markers, and
expressed low levels of CD11c and F4/80
and high levels of MHC class II (MHCIIhi , CD11clo , F4/80lo , CD3− , B220− , CD4− ,
CD8α− , CD11b− , and GR-1− ). In a parallel
report, Hurst et al. (67) identified a similar
cell that was responsible for IL-5 production
in response to IL-25. This population was lost
in mice doubly deficient for RAG-2 and the
common γ chain, which lack, in addition to
lymphocytes, cells of NK, γδ T cell lineages,
and perhaps other cells of hematopoietic origin. Thus, the IL-25-responsive cell type is
likely of hematopoietic origin and dependent
on common γ chain cytokines for its development (or perhaps responsiveness to IL-25). An
uncharacterized innate immune cell, present
in many different tissues, may therefore be responsible for IL-25-induced expression of IL5 and IL-13, and possibly IL-4. Collectively,
these data support a model in which IL-25
production by Th2 cells markedly amplifies
type 2 responses through both adaptive and
innate immune cells.
Subsequent reports identified a critical
role for IL-25 in host defense to parasitic
helminthes (125, 126). Fallon et al. (125) examined the host response to Nippostrongy-
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lus brasiliensis in wild-type or IL-25-deficient
mice and found IL-25 critical for an early
burst of type 2 cytokines that facilitates rapid
worm expulsion but not essential for eventual pathogen clearance or Th2 response.
Thus, although IL-25 deficiency blunted the
early induction of IL-5 and IL-13, it did not
prevent a late, IL-25-independent response.
Administration of IL-25 to IL-25-deficient
mice enhanced N. brasiliensis clearance via a
type 2 cytokine-dependent mechanism and
could reconstitute parasite clearance in RAGdeficient mice. Therefore, IL-25 induced a
type 2 cytokine response sufficient to eliminate parasitic infection, via a T cell– and B
cell–independent mechanism. As in the study
of Fort et al. (42), the target for IL-25’s actions
was identified as a CD19− , CD4− , CD8−
(non-B, non-T), c-kit+ , FcεRI− cell found in
mesenteric lymph nodes of infected wild-type,
but not IL-25-deficient, mice. Expansion of
this cell population was induced by IL-25 administered to wild-type and RAG-deficient
mice, as well as mice pan-deficient for Th2
cytokines (Il4−/− , Il5−/− , Il9−/− , Il13−/− ). A
unique population of c-kit+ cells was induced
in an IL-25-dependent and lymphocyte- and
type 2 cytokine–independent manner (125).
Interestingly, IL-25 induced the production
of IL-5 and IL-13 protein in this cell population, but only IL-4 mRNA; IL-4 protein
production could not be demonstrated. Thus,
in agreement with previous studies, IL-25 appears to act on a novel cell population whose
production of type 2 cytokines is independent
of Th2 cells.
Owyang et al. (126) examined the role of
IL-25 in defense against another helminthic
parasite infection, Trichuris muris. In response
to T. muris challenge, IL-25-deficient mice
demonstrated significantly reduced induction
of type 2 cytokines (IL-4 and IL-13) but
elevated type 1 cytokines (IFN-γ). This
response was accompanied by diminished induction of IgG1 and IgE, diminished goblet cell hyperplasia, and failure to eradicate
worm burden. A mouse strain susceptible
to T. muris infection (AKR) was successfully
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treated by administration of IL-25, which
resulted in reconstitution of a type 2 response typical of resistant strains (BALB/c
and C57Bl/6). Consistent with these findings, resistant strains of mice demonstrated
increased IL-25 and IL-17RB mRNA in the
intestines of unchallenged animals. In an effort to identify the cellular source of IL25, an IL-25-lacZ knock-in reporter system was developed, with which CD4+ and
CD8+ T cells were identified in the cecal
patch (analog of the human appendix) (126).
No reporter expression was found in B cells
(CD19+ ), basophils or mast cells (FcεRI+ ),
eosinophils (CCR3+ ), NK cells (NK1.1+ ),
DCs (CD11c+ ), or macrophage/monocytes
(CD11b+ ). Thus, IL-25 appears to be constitutively expressed by subpopulations of CD4
and CD8 T cells found in the cecum of normal
mice. Unfortunately, analyses of IL-25/lacZpositive cells for coexpression of other Th2
cytokines (e.g., IL-4) were not reported, raising the possibility that the IL-25+ cells might
not be synonymous with classical Th2 cells.
Owing to the enhanced type 1 response observed in the absence of IL-25, Owyang et al.
(126) treated T. muris-infected mice with antiIL-12 and anti-IFN-γ. Remarkably, neutralization of the Th1 pathway resulted in restitution of an effective Th2 response to parasitic
helminthic infection despite IL-25 deficiency.
Furthermore, the development of chronic infection in IL-25-deficient mice infected with
T. muris resulted in a florid colitis that was
associated with elevated intestinal production
of IFN-γ and IL-17. Similarly, IL-25 deficiency resulted in high susceptibility to EAE
that was associated with elevated CNS infiltration by Th17 cells. Collectively, these data
suggest that IL-25 may play a dual role in
host protection: enhanced induction of type
2 responses and suppression of type 1, or perhaps Th17, responses. Additional studies are
needed to clarify the mechanism by which IL25 deficiency leads to enhanced type 1 or type
17 responses, although this may not be dissimilar to previous reports in which deficient
type 2 immunity based on cytokine blockade
or signaling deficiency (e.g., GATA3) leads to
a default enhancement of type 1 immunity.
CONCLUDING REMARKS
Bioinformatics-based discovery in the genomic/postgenomic era has propelled the
identification and characterization of new
members of the IL-12 and IL-17 cytokine
families that have led in turn to discovery of
a new arm of the adaptive immune response
(Th17) and an important new player in another arm (Th2). IL-17 cytokines are now
centrally positioned as products of two of the
three arms of effector CD4 T cell lineages:
IL-17A and IL-17F in Th17 and IL-25 in
Th2. Particularly striking has been the identification of new members of the IL-12 family
cytokines, IL-23 and IL-27, and IL-6, prototype for IL-12 cytokines, as innate immune
cell products that control Th17 responses.
Perhaps it is fitting that IL-6, patriarch of
this extended family, has lately become appreciated as a key danger signal that switches
the otherwise proregulatory cytokine, TGFβ, into a Th17-diverting mediator, making it a
pivotal cytokine in self-nonself discrimination
(56, 127).
In a broad sense, members of the IL-6 superfamily can now be viewed as integrators of
more primitive type 1 and type 17 immunity,
which probably evolved to handle simpler
types of infectious agents, such as viruses, bacteria, protozoal parasites, and perhaps fungi.
IL-12 is central to Th1 responses, whereas
IL-6 and IL-23 are central to Th17. IL-27
may modulate the balance between Th1 and
Th17, extinguishing Th17 development in
favor of Th1. Whether this serves to facilitate transition from early Th17-dominated
responses to late Th1-dominated responses,
serves to dampen the risk of Th17-mediated
autoimmunity, or both remains to be determined. In contrast, Th2 responses, and the
cytokines that define them (IL-4, IL-5, and
IL-13), probably evolved only later,
as more complex multicellular organisms became hosts for more complex
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pathogens—such as parasitic helminthes.
IL-25 appears to have developed to orchestrate the adaptive and innate mechanisms for
eradicating these pathogens. Regardless of
origins, a common theme is that T cells have
leveraged IL-17 family members to mobilize
the rapid cellular responders of type 17
and type 2 immunity—the granulocytes—to
enhance pathogen clearance.
The impact of the discovery of the IL-17
cytokines and the Th17 pathway for treatment
of human disease is likely to be profound. The
Th17 lineage is now implicated in a number of
autoinflammatory disorders, including some
previously associated with Th1 dysregulation:
rheumatoid arthritis, multiple sclerosis, IBD,
and psoriasis, as well as others likely to be defined. The Th17 arm has also been implicated
in allograft rejection. The identification of IL17 family participation in allergic diseases is
equally promising. As our understanding of
the pathways and mediators responsible for
these diseases becomes better defined, so too
will the therapies, with attendant lessening of
untoward treatment risks. Existing therapies
that target common proinflammatory mediators (e.g., TNF-α) have relatively high risk
for infectious complications. Similarly, recent
strategies based on administration of anti-p40
neutralizing antibodies have shown excellent
clinical efficacy for IBD, but are also associated with a high risk of infection (128), owing
to their inhibition of both type 1 and type 17
immunity. In this regard, the efficacy of IL23 ablation for mouse models of autoimmunity has been compelling, and, notably, IL-23deficient mice remain resistant to intracellular pathogens such as Mycobacterium, Listeria,
Toxoplasma, and Leishmania, whereas IL-12and p40-deficient mice are highly susceptible. Thus, there is good reason to hope that
IL-23- and IL-17-targeting therapies will be
highly effective in controlling certain autoinflammatory disorders, with decreased risk of
infectious complications. New vaccine strategies for enhanced protection against type
17 and type 2 pathogens are also likely to
result.
ACKNOWLEDGMENTS
The authors thank Drs. Sarah Hymowitz and Melissa Starovasnik for permission to use figures,
and Dr. Dan Littman for sharing a manuscript in advance of publication. We thank members
of the Weaver lab for helpful comments and suggestions. Finally, we thank Noelle LeLievre for
editorial assistance. We offer our apologies to colleagues whose work could not be adequately
cited or discussed owing to space limitations. This work was supported by grants from the NIH
(C.T.W., P.R.M., and R.D.H.), the Crohn’s and Colitis Foundation of America and National
Multiple Sclerosis Society (L.E.H. and C.T.W.), and Sankyo Co. Ltd. (C.T.W.).
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Contents
Volume 25, 2007
Frontispiece
Peter C. Doherty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x
Challenged by Complexity: My Twentieth Century in Immunology
Peter C. Doherty p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p1
The Impact of Glycosylation on the Biological Function and Structure
of Human Immunoglobulins
James N. Arnold, Mark R. Wormald, Robert B. Sim, Pauline M. Rudd,
and Raymond A. Dwek p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 21
The Multiple Roles of Osteoclasts in Host Defense: Bone Remodeling
and Hematopoietic Stem Cell Mobilization
Orit Kollet, Ayelet Dar, and Tsvee Lapidot p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 51
Flying Under the Radar: The Immunobiology of Hepatitis C
Lynn B. Dustin and Charles M. Rice p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 71
Resolution Phase of Inflammation: Novel Endogenous
Anti-Inflammatory and Proresolving Lipid Mediators and Pathways
Charles N. Serhan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p101
Immunobiology of Allogeneic Hematopoietic Stem Cell
Transplantation
Lisbeth A. Welniak, Bruce R. Blazar, and William J. Murphy p p p p p p p p p p p p p p p p p p p p p p p139
Effector and Memory CTL Differentiation
Matthew A. Williams and Michael J. Bevan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p171
TSLP: An Epithelial Cell Cytokine that Regulates T Cell
Differentiation by Conditioning Dendritic Cell Maturation
Yong-Jun Liu, Vasilli Soumelis, Norihiko Watanabe, Tomoki Ito,
Yui-Hsi Wang, Rene de Waal Malefyt, Miyuki Omori, Baohua Zhou,
and Steven F. Ziegler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p193
Discovery and Biology of IL-23 and IL-27: Related but Functionally
Distinct Regulators of Inflammation
Robert A. Kastelein, Christopher A. Hunter, and Daniel J. Cua p p p p p p p p p p p p p p p p p p p p p p221
v
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Improving T Cell Therapy for Cancer
Ann M. Leen, Cliona M. Rooney, and Aaron E. Foster p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p243
Immunosuppressive Strategies that are Mediated by Tumor Cells
Gabriel A. Rabinovich, Dmitry Gabrilovich, and Eduardo M. Sotomayor p p p p p p p p p p p p267
The Biology of NKT Cells
Albert Bendelac, Paul B. Savage, and Luc Teyton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p297
Annu. Rev. Immunol. 2007.25:821-852. Downloaded from arjournals.annualreviews.org
by CNRS-multi-site on 12/06/07. For personal use only.
Regulation of Cellular and Humoral Immune Responses by the SLAM
and SAP Families of Molecules
Cindy S. Ma, Kim E. Nichols, and Stuart G. Tangye p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p337
Mucosal Dendritic Cells
Akiko Iwasaki p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p381
Immunologically Active Autoantigens: The Role of Toll-Like
Receptors in the Development of Chronic Inflammatory Disease
Ann Marshak-Rothstein and Ian R. Rifkin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p419
The Immunobiology of SARS
Jun Chen and Kanta Subbarao p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p443
Nonreceptor Protein-Tyrosine Phosphatases in Immune Cell Signaling
Lily I. Pao, Karen Badour, Katherine A. Siminovitch, and Benjamin G. Neel p p p p p p p473
Fc Receptor-Like Molecules
Randall S. Davis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p525
The Death Domain Superfamily in Intracellular Signaling of Apoptosis
and Inflammation
Hyun Ho Park, Yu-Chih Lo, Su-Chang Lin, Liwei Wang, Jin Kuk Yang,
and Hao Wu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p561
Cellular Responses to Viral Infection in Humans: Lessons from
Epstein-Barr Virus
Andrew D. Hislop, Graham S. Taylor, Delphine Sauce, and Alan B. Rickinson p p p p p p587
Structural Basis of Integrin Regulation and Signaling
Bing-Hao Luo, Christopher V. Carman, and Timothy A. Springer p p p p p p p p p p p p p p p p p p p619
Zoned Out: Functional Mapping of Stromal Signaling
Microenvironments in the Thymus
Howard T. Petrie and Juan Carlos Zúñiga-Pflücker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p649
T Cells as a Self-Referential, Sensory Organ
Mark M. Davis, Michelle Krogsgaard, Morgan Huse, Johannes Huppa,
Bjoern F. Lillemeier, and Qi-jing Li p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p681
The Host Defense of Drosophila melanogaster
Bruno Lemaitre and Jules Hoffmann p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p697
vi
Contents
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Ontogeny of the Hematopoietic System
Ana Cumano and Isabelle Godin p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p745
Chemokine:Receptor Structure, Interactions, and Antagonism
Samantha J. Allen, Susan E. Crown, and Tracy M. Handel p p p p p p p p p p p p p p p p p p p p p p p p p p787
IL-17 Family Cytokines and the Expanding Diversity of Effector
T Cell Lineages
Casey T. Weaver, Robin D. Hatton, Paul R. Mangan, and Laurie E. Harrington p p p821
Annu. Rev. Immunol. 2007.25:821-852. Downloaded from arjournals.annualreviews.org
by CNRS-multi-site on 12/06/07. For personal use only.
Indexes
Cumulative Index of Contributing Authors, Volumes 15–25 p p p p p p p p p p p p p p p p p p p p p p p p853
Cumulative Index of Chapter Titles, Volumes 15–25 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p860
Errata
An online log of corrections to Annual Review of Immunology chapters (if any, 1997 to
the present) may be found at http://immunol.annualreviews.org/errata.shtml
Contents
vii