Structure and signalling in the IL-17 receptor superfamily

Sarah L. Gaffen
1
1
University of Pittsburgh, Department of Medicine, Division of Rheumatology and Clinical
Immunology, Pittsburgh, PA 15261. Ph. 412-383-8903. [email protected]
Preface
Interleukin-17 (IL-17; also known as IL-17A), the hallmark cytokine of the newly-defined T
helper 17 (T
H
17) cell subset has important roles in protecting the host against extracellular
pathogens, but conversely promotes inflammatory pathology in autoimmune disease. IL-17A
and its receptor (IL-17RA) are the founding members of a new subfamily of cytokines/
receptors, with unique structural features that distinguish them from other cytokine subclasses.
Research defining the signal transduction pathways mediated by IL-17-family cytokines has
lagged behind other receptors, but studies in the past 2 years have begun to delineate unusual
functional motifs and novel proximal signaling mediators used by the IL-17R family to mediate
downstream events.
In 1986, a seminal paper by Coffman and Mosman postulated the existence of subsets of T
helper (T
H
) cells characterized by differential secretion of cytokines, designated T
H
1 and
T
H
2 cells [G]
1
. Although this viewpoint dominated for nearly 2 decades
2
, discrepancies arose
as details of T
H
cell development became more refined. In particular, deficiency of
interleukin-12 (IL-12) (specifically, the IL-12p40 subunit of this heterodimeric cytokine),
which drives the T
H
1 cell lineage, frequently failed to phenocopy deficiency of interferon-
(IFN), the hallmark T
H
1 cell cytokine
3
. The basis for this paradox became evident when it
was recognized that IL-12p40 is also a constituent of IL-23 (together with IL-23p19), and so
IL-12p40-deficient mice lack both IL-12 and IL-23
4
. Further studies showed that IL-23
stimulates IL-17A production in a subset of CD4+T cells
5, 6
, and IL-23p19-deficient mice
but not IL-12p35-deficient mice are susceptible to certain autoimmune diseases
7
. This revealed
a new branch of the T
H
cell family tree, now known as T
H
17 cells [G] (TIMELINE).
Numerous reports rapidly followed, describing the factors involved in differentiation of this
lineage, the additional cytokines produced by T
H
17 cells, and the production of T
H
17-type
cytokines by other cell types. To summarize briefly, T
H
17 cells are driven to differentiate by
transforming growth factor- (TGF), IL-1, and IL-6, and IL-23 is required to expand and
stabilize the population. The transcription factors signal transducer and activator of
transcription 3 (STAT3), retinoic acid receptor-related orphan receptor-t (RORt) and AHR
(aryl hydrocarbon receptor) control T
H
17 cell differentiation. In addition to IL-17, T
H
17 cells
produce IL-17F (this cytokine is discussed in subsequent sections), IL-21, IL-22 and IL-26, as
well as chemokines including CCL20/MIP3. T
H
17 cells function prominently at mucosal
surfaces, and trigger pro-inflammatory danger signals that promote neutrophil mobilization
and the expression of anti-microbial factors. Conversely, T
H
17 cells drive inflammatory
pathology in various autoimmune conditions. Finally, various T
H
17-like cells exist, which
produce a similar array of cytokines; these include T cells [G], natural killer (NK) cells and
NKT cells, and LTi (lymphoid tissue inducer) [G] cells. The reader is referred to several
excellent reviews on this topic
8-10
.
Less attention has been paid to the mechanisms by which IL-17 family cytokines mediate
effects at a molecular level. IL-17A and its receptor are founding members of a new subfamily
NIH Public Access
Author Manuscript
Nat Rev Immunol. Author manuscript; available in PMC 2010 August 1.
Published in final edited form as:
Nat Rev Immunol. 2009 August ; 9(8): 556. doi:10.1038/nri2586.
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of cytokines (IL-17A-F) and receptors (IL-17RA-RE) (Table 1). The IL-17R family has unique
structural features and mediates signalling events that are surprisingly distinct from other
cytokines, particularly those usually involved in adaptive immunity. Whereas the signature
cytokines involved in the T
H
1 and T
H
2 cell lineages trigger J AKSTAT signalling pathways,
IL-17-family cytokines mediate signalling through a novel ACT1-dependent pathway,
culminating in the activation of pro-inflammatory factors such as NF-B that are usually
associated with innate immune signalling (Box 1). So, by virtue of the unusual signalling
properties of IL-17, T
H
17 cells act as a bridge between adaptive and innate immunity
11
. Recent
work has begun to define the architecture of the IL-17 family, and its sometimes surprising
ligandreceptor relationships and signal transduction pathways. This article reviews recent
discoveries in this field in the context of cytokine receptor biology as well as the potential
implications of this knowledge with respect to emerging therapeutics.
IL-17A cytokines constitute a unique subfamily
IL-17A was identified by a subtractive hybridization screen in a rodent T cell library
12
(TIMELINE). Due to its unusual amino acid sequence, it was not immediately recognized as
a cytokine. Subsequent characterization showed that IL-17A is produced by T cells and
stimulates the production of factors such as granulocyte colony-stimulating factor (G-CSF),
IL-6 and IL-8, indicating that it should be considered a bona fide cytokine
13, 14
. Intriguingly,
the amino acid sequence of IL-17A is 58% identical to an open reading frame in Herpesvirus
saimiri, a T cell-tropic -herpesvirus
13
(known as vIL-17), although the significance of
homology to a viral protein remains unknown. Genomic sequencing efforts led to the
identification of several putative IL-17A homologues, IL-17BIL-17E. The only member of
the family to have been crystallized for structural studies is IL-17F, which adopts a 3-
dimensional cystine-knot fold architecture
15
. IL-17-family homologues have been found in a
variety of species, including sea lamprey [Lethenteron japonicum), rainbow trout
[Oncorhynchus mykiss], zebraflsh (Dario rerio) and worms (Caenorhabditis elegans], among
others
16
. Although the cellular sources and expression patterns of the various mammalian
IL-17 family members are different (Table 1), all have pro-inflammatory activities (see below).
IL-17A and IL-17F drive inflammation and autoimmunity
IL-17A and IL-17F, eponymous cytokines of the T
H
17 cell lineage, are by far the best
characterized. Both are covalent homodimers, and recent findings show that they also form
IL-17AIL-17F heterodimers (Figure 1)
17, 18
. IL-17AIL-17F heterodimers are produced at
higher levels than IL-17A homodimers by human peripheral blood mononuclear cells in
vitro
17
, but the form that predominates in vivo is not well defined
19
. IL-17A, IL-17F and
IL-17AIL-17F all signal through the same receptor subunits, IL-17RA and IL-17RC, which
together form a heteromeric complex
20, 21
. Nonetheless, IL-17A and IL-17F have distinct
biological effects. Studies comparing Il17a
-/-
mice with Il17f
-/-
mice indicate that IL-17A
seems to have a more central role in driving autoimmunity than IL-17F, probably due to its
more potent strength of signalling
19, 22
,. The role of the IL-17AIL-17F heterodimer in vivo
will be more challenging to evaluate. The basis for functional differences between IL-17A and
IL-17F could be the markedly decreased strength of signalling triggered by IL-17F compared
with IL-17A, as IL-17F responses are 1030-fold weaker in terms of downstream gene
activation than those of IL-17A, with IL-17AIL-17F heterodimers acting at an intermediate
level
17, 23, 24
. The precise nature of their respective receptor complexes has not been defined
(see also IL-17RC section below). As IL-17RA and IL-17RC have very different affinities
for IL-17A and IL-17F, it is plausible that different complexes exist with varying ratios of
IL-17RA and IL-17RC, which manifest different ligand preferences (Figure 1).
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IL-17E is a T
H
2 cell-promoting cytokine
IL-17E, commonly known as IL-25, is produced by mucosal epithelial cells, as well as by
multiple immune cell types (Table 1). Transgenic overexpression of IL-25 promotes
eosinophilia and stimulates the production of T
H
2 cell-specific cytokines. Moreover, IL-25
limits T
H
17 cell development by inducing the expression of IL-13 by dendritic cells (DCs) or
by inhibiting IL-23 production by macrophages (reviewed in Ref.
25
). IL-25 binds a receptor
complex composed of IL-17RB (also known as IL-25R), which partners with IL-17RA (Figure
1)
26
. Il17rb
-/-
and Il17ra
-/-
mice fail to respond to IL-25, and both knockout strains are
refractory to pulmonary inflammation induced by intranasal application of IL-25
27
.
Consequently, there is intriguing crosstalk between members of the IL-17 cytokine family.
IL-17B, -C and -D functions are poorly defined
IL-17B, IL-17C and IL-17D remain poorly characterized. IL-17B binds to IL-17RB with fairly
high affinity
28
, and IL-17C was recently reported to bind IL-17RE and to activate nuclear
factor-B (NF-B) (S. Levin, personal communication). The receptor(s) for IL-17D remains
unknown. Ectopic expression of IL-17B and IL-17C by CD4+T cells exacerbates collagen-
induced arthritis [G] (CIA)
29
, and intranasal administration of adenoviruses expressing
IL-17C, IL-17A or IL-17F triggers comparable neutrophilic responses
30
, suggesting that these
cytokines mediate common biological effects, probably through shared signalling pathways.
Antibodies specific for IL-17B also partially suppress CIA
29
. IL-17B and IL-17C stimulate
expression of an array of pro-inflammatory genes similar to those induced by IL-17A and
IL-17F
29, 31
. IL-17D was reported to promote a pro-inflammatory gene expression profile in
endothelial cells, and it had a mild inhibitory effect on myeloid progenitor cell proliferation
in vitro
32
. As more knockout mice are generated and the target receptors for IL-17B, IL-17C
and IL-17D become more clearly defined, we will gain an improved understanding of these
newer IL-17 family members.
The IL-17 receptor family
The IL-17R family comprises five receptor subunits IL-17RAIL-17RE
33
(Figure 1). Despite
considerable sequence divergence, many of the genes encoding the IL-17R family are linked,
with clusters on human chromosome 3 (for IL-17RB, IL-17RC, IL-17RD and IL-17RE) and
mouse chromosomes 6 (IL-17RA, IL-17RC and IL-17RE) and 14 (IL-17RB and IL-17RD).
All are single transmembrane domain-containing receptors, ranging in size from 499866
amino acids (with smaller alternatively spliced forms also found, discussed below). These
receptor subunits contain certain conserved structural motifs, including an extracellular
fibronectin III-like domain and a cytoplasmic SEFIR domain (see below). Although it is still
not clear precisely how IL-17R subunits interact to form productive receptor complexes, it
becoming evident that IL-17RA, by far the largest member of the family, is a common
signalling subunit used by multiple ligands.
IL-17RA: expression and complex formation
IL-17RA was initially identified as the receptor for mammalian IL-17A and vIL-17
13
.
IL-17RA also binds IL-17F, albeit weakly, and is necessary for IL-17A-, IL-17AIL-17F- and
IL-17F-mediated signal transduction
15
. Early studies showed that the affinity of IL-17RA for
IL-17A is lower than the concentration required to mediate responses, which indicates that an
additional subunit is involved in binding ligand and/or eliciting signalling
34
. Indeed, IL-17RA
partners with IL-17RC to induce responses to IL-17A and IL-17F
35
. Similarly, Il17ra
-/-
mice
are refractory to the effects of IL-25, suggesting that IL-17RA is also a component of this
receptor complex
27
. Moreover, IL-17RA might associate with IL-17RD, as these subunits co-
localize, and overexpression of a mutant IL-17RD lacking a cytoplasmic tail inhibits IL-17A-
dependent signals
36
. However, this finding has yet to be validated, and no ligand has been
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identified for an IL-17RAIL-17RD pairing (Figure 1). Based on its usage by multiple
cytokines, IL-17RA may thus be analogous to common cytokine receptor subunits such as
gp130 in the IL-6 family
37
.
IL-17RA is expressed ubiquitously, with particularly high levels in haematopoietic tissue
13,
22
. This expression pattern is curious, as the main responses to IL-17A occur in epithelial,
endothelial and fibroblast cells, although macrophages and DCs are also responsive (reviewed
in Ref.
38
). Only a limited number of IL-17A-induced genes in lymphocytes have been
documented, which are quite distinct from genes induced by IL-17A in other cell types
22,
39
. Although its expression is widespread, IL-17RA can be dynamically regulated. For
example, IL-15 and IL-21 upregulate expression of IL-17RA in CD8+T cells
40, 41
, and
phosphoinositide 3-kinase (PI3K) limits IL-17RA expression in T cells. This could be
biologically significant, because IL-17A-induced signalling strength correlates with cell
surface expression levels of IL-17RA; in contrast to most cytokine receptors, high levels of
IL-17RA seem to be required for effective responses
42, 43
. Another function of IL-17RA might
be to limit signalling by receptor-mediated internalization of ligand. Surface expression of
IL-17RA rapidly decreases after IL-17 binding, theoretically internalizing IL-17A and clearing
it from the inflammatory milieu
41
.
The composition of IL-17RA-containing complexes is poorly defined. The textbook paradigm
of cytokine receptor signalling is that individual subunits reside in the membrane as monomers.
Ligand binding promotes subunit oligomerization, thereby juxtaposing receptor-associated
signalling intermediates such as kinases or adaptors. Inconsistent with this view are studies
showing that many receptors actually exist as pre-associated, multi-subunit complexes (such
as TLRs, tumour necrosis factor receptors (TNFRs), and erythropoietin receptor (EPOR);
reviewed in Refs.
38, 44
). Mechanistically, pre-assembly poises a receptor to respond rapidly
and specifically to ligand. In the case of the IL-17R, studies using fluorescence resonance
energy transfer [G] (FRET) to analyse interactions between IL-17RA subunits showed that
IL-17RA forms ligand-independent complexes
45-47
. Moreover, IL-17RA co-
immunoprecipitated with IL-17RC in overexpression studies in a ligabd-dependent manner,
although it is not known whether IL-17RC is pre-assembled with IL-17RA to any degree
35
.
The precise stoichiometry of the IL-17A-binding complex has not been determined, but native
gel analyses of IL-17RC are consistent with a trimeric complex containing two IL-17RA
subunits and one IL-17RC subunit
48
.
For pre-assembled receptors such as the EPOR, ligand binding induces large conformational
changes in the relative positions of the receptor subunits. This re-orients receptor-bound
cytoplasmic signalling molecules such as J AKs, facilitating interactions with appropriate
substrates
49
. This might be the case for IL-17RA, because FRET between IL-17RA molecules
decreases after interaction with ligand
45, 46
. One possible scenario is that IL-17RA dimers
dissociate and are replaced by IL-17RAIL-17RC heterodimers. Alternatively, IL-17RC might
be recruited to the IL-17RA dimer to create a trimer or larger multimer, together with
cytoplasmic signalling molecules such as ACT1 (also known as TRAF3IP2 and CIKS). A
better understanding of this process awaits the IL-17R crystal structure.
In the TNFR system, pre-assembly is dictated by an extracellular cysteine-rich motif known
as a pre-ligand assembly domain (PLAD). Soluble PLAD peptides have been shown to prevent
TNFR assembly and thus block signalling in CIA
50
. Although it is structurally distinct from
TNF receptors, IL-17RA encodes a fibronectin III-like domain (FN) PLAD that dimerizes in
a yeast two-hybrid system and is required for co-immunoprecipitation of IL-17RA dimers
45
Unlike the TNF system, where the PLAD and ligand-binding site of the receptor are physically
discrete, the IL-17RA FN2 motif is also an essential component of the IL-17A-binding domain
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45
. Strategies to block IL-17A or its receptor could therefore include soluble PLADs as well
as antibodies or soluble receptors
47
IL-17RA signalling: the NF-B pathway
As IL-17RA lacks homology to known receptors
13
, it was not possible to investigate signal
transduction simply by comparison with other cytokine receptor systems. However, studies
defining IL-17A-induced genes showed that IL-17A activates a highly pro-inflammatory
programme of gene expression, typical of that induced by innate immune receptors such as
IL-1R and TLRs
51, 52
. Similar to these receptors, IL-17A activates nuclear factor-B (NF-
B), a hallmark transcription factor associated with inflammation (Figure 3A)
13
.
Correspondingly, DNA elements that bind NF-B in the promoters of several IL-17A target
genes are required for IL-17A-induced gene expression (reviewed in Ref.
38
). Gel shift studies
indicated that IL-17A activates p50 and p65, which are components of the classical NF-B
pathway [G]
53
. So far, there is no evidence that the non-classical NF-B pathway [G] is
involved in IL-17RA signalling (S.L.G., unpublished observations). However, NF-B-
inducing kinase (NIK), which can mediate events in the non-classical pathway, was reported
to be activated in response to IL-17A
54
. IL-17A also induces the expression of IB
51, 55
,
which is a positive regulator of transcription by the TLR and IL-1R pathways
55
. Although it
has not been clearly defined for IL-17A, it is likely that IB is involved in IL-17A-dependent
gene expression.
A wide diversity of inflammatory stimuli activate NF-B, but they accomplish this through
distinct proximal signalling pathways
56
. For considerable time, the proximal activators of NF-
B in the IL-17R pathway remained obscure. Hints came from observations that IL-17A
signalling had parallels to IL-1R and TLR signalling cascades. For example, TRAF6 is a key
adaptor in the IL-1R/TLR signalling cascade, and fibroblast cells from Traf6
-/-
mice are
defective in IL-17A-mediated induction of NF-B
57
. However, the lack of an obvious TRAF6-
binding motif in IL-17RA suggested that a signalling intermediate might be required to bridge
IL-17RA and TRAF6. However, molecules involved in proximal IL-1R signalling, such as
MYD88 (myeloid differentiation primary response gene), TRIF (TIR domain containing
adaptor-inducing interferon-), IRAK4 (IL-1R-associated kinase 4) and IRAK1, are
dispensable for IL-17A-dependent signalling
43, 58
(F. Shen, L. Li and S.L.G., unpublished
data). Consequently, early IL-17R signalling events are distinct from classical activators of
innate immune responses (Figure 3B).
A key insight into IL-17R signaling emerged from a bioinformatics analysis that identified a
conserved motif in the cytoplasmic domains of IL-17R-family members with homology to the
Toll/IL-IR (TIR) domain [G]
59
. TIR domains provide essential and specific docking sites for
intracellular adaptors such as MYD88. This study named the conserved IL-17R region a SEFIR
domain, for SEF (similar expression to FGF receptor) /IL-17R. SEFIR domains lack certain
elements found in prototypical TIR domains, potentially explaining why they do not engage
TIR-containing adaptors. Specifically, SEFIR domains lack the TIR Box 3 subdomain and the
BB-loop [G]
59
, which are crucial specificity determinants directing TIR-based proteinprotein
interactions
60
. Strikingly, a region C-terminal to the SEFIR domain in IL-17RA has marked
sequence homology to BB-loops. Deletion of or point mutations in this region render IL-17RA
non-functional, and so this motif is referred to as a TIR-like loop (TILL)
43, 61
. It is probable
that the TILL provides a unique interaction surface for an as-yet-unknown signalling molecule,
potentially serving as the Box 3 equivalent. Surprisingly, although all IL-17R receptors have
a SEFIR motif, the TILL domain appears to be unique to IL-17RA, perhaps explaining why
IL-17RA functions as a shared subunit (Figure 1).
A SEFIR domain is also present in ACT1, a signalling adaptor that was previously linked to
NF-B activation through BAFF (B cell activating factor) and CD40L
59
. Indeed, an ACT1
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deficiency in knockout mice or generated by RNA interference-mediated knockdown impairs
IL-17A- and IL-17F-induced activation of NF-B
25, 62
(Figure 3). Co-immunoprecipitation
studies indicate that ACT1 is recruited to IL-17RA within 5 minutes of IL-17A stimulation
63
. Supporting these observations, deletion of the SEFIR domain in IL-17RA impairs activation
of NF-B by IL-17A
43, 63
. Unlike IL-17RA, ACT1 contains a TRAF6-binding motif, and
accordingly can bind TRAF6, TRAF3 and TAK1
63
. However, Act1
-/-
cells are still capable of
delayed activation of ERK1/2
63
, indicating that ACT1-independent pathways are also
mediated by IL-17RA. The crucial role of ACT1 in IL-17A signalling has recently been verified
in a second knockout mouse model
26
. Intriguingly, a respiratory pathogen, Chlamydia
pneumoniae, encodes an Act1-binding protein that appears to inhibit IL-17A-mediated
signalling, presumably providing a survival advantage to this organism
64
. Collectively, these
studies illustrate that the proximal events in IL-17R-mediated activation of NF-B are different
from TLR/IL-1R due to unique structural components of IL-17 receptors (Figure 3B).
IL-17RA signalling: AP1, MAPK and mRNA stability
Another typical event induced by pro-inflammatory mediators is activation of the mitogen-
activated protein kinase (MAPK) pathway, which leads to the activation of AP1 transcription
factors. IL-17A activates various MAPKs, but ERK is generally the most strongly and rapidly
phosphorylated. Although AP1 binding sites are enriched in IL-17A target promoters
42
, the
AP1 site in the mouse Il6 promoter is dispensable for IL-17A-mediated activation
53
. In general,
the MAPK pathway has a more important role in regulating the expression of IL-17A-induced
genes through control of mRNA transcript stability. MAPK stabilizes mRNA through the
inhibition of destabilizing proteins such as tristetraprolin (TTP). TTP binds to AU-rich
elements (AREs) in mRNA transcripts and delivers them to the exosome complex [G],
whereupon they are degraded. Phosphorylation of TTP by MAPK blocks its ability to recruit
the degradative machinery, thereby increasing mRNA transcript half-life (Reviewed in Ref
65
). Many IL-17A target genes are chemokines or cytokines whose transcripts are stabilized
by AREs located in the 3 UTR
65
. Numerous studies show that activation of MAPK by IL-17A
increases the concentration of these transcripts signiflcantly
38
. ACT1 is required for IL-17A-
mediated stabilization of CXCL1 (also known as Gro or KC) mRNA, but TRAF6 is
surprisingly dispensable
66
. Unexpectedly, the ability of IL-17A to stabilize TNF-induced
CXCL1 mRNA is not compromised in Ttp-deficient fibroblasts (T. Hamilton, personal
communication). In addition to TTP, other proteins are involved in mediating cytokine mRNA
stability such as the recently described Zc3hl2a gene
67
. Thus, there is clearly much more to
learn about the mechanisms by which IL-17A regulates transcript stability, but this is likely to
be a very important means by which inflammation is controlled by IL-17.
IL-17RA signalling: C/EBP
IL-17A is consistently found to be a weak activator of NF-B, suggesting the involvement of
additional transcription factors in the response to IL-17. A microarray screen for IL-17A-
induced genes identified the CCAAT/enhancer binding protein transcription factors C/EBP
and C/EBP
53
. The promoters of genes upregulated by IL-17A are enriched for C/EBP binding
elements
42
, and activation of the Il6 and lcn2 (lipocalin 2, also known as 24p3) promoters
have an absolute requirement for C/EBP/ following IL-17A stimulation
53
. So, C/EBP and
C/EBP are targets of IL-17A signalling and also important mediators of IL-17A-induced
signalling pathways.
In some respects, C/EBP and C/EBP seem to function redundantly, as reconstitution of C/
EBP-deficient cells with either transcription factor can restore IL-17A-dependent induction
of IL-6 or lipocalin 2 expression
53
. Nonetheless, there are essential differences in how C/
EBP and C/EBP are regulated by IL-17RA. ACT1 and the SEFIR and TILL domains of
IL-17RA are required for the induction of C/EBP expression, suggesting a role for NF-B
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43, 58
. This observation is consistent with a study showing that NF-B can bind directly to the
C/EBP promoter after LPS stimulation
68
.
C/EBP expression is regulated by IL-17A in a more complex manner. C/EBP exists in three
isoforms that are generated by alternative translation
69
. The largest is a full length isoform
known as liver enriched activator protein (LAP*). A shorter form, LAP, is generated from an
alternative start codon and is thought to be the most transcriptionally active form of C/EBP.
LIP (liver-enriched inhibitory protein) is also generated by alternative translation, and acts as
a dominant negative inhibitor. The mechanism underlying these alternative translation events
is not understood. IL-17A treatment of fibroblast cell lines results in a mild induction of LAP,
a large increase in LAP* and no induction of LIP. Induction of LAP* depends on the SEFIR/
TILL domain of IL-17RA, suggesting that this process is downstream of ACT1. Generation
of LAP* also requires a poorly-characterized C-terminal domain in IL-17RA known as a C/
EBP-activation domain (C-BAD)
43
, which is not found in any other IL-17R family members
61
.
As with many signaling effectors, post-translational modifications of C/EBP such as
phosphorylation are important for its activity
69, 70
. IL-17A triggers dual, sequential
phosphorylation of a regulatory site within C/EBP. ERK phosphorylates one site (Thr-188)
within 15 minutes of IL-17A stimulation. However, GSK (glycogen synthase kinase)-3
phosphorylates Thr-179 only after 1 hour, an event that requires prior phosphorylation at
Thr-188
61
. Interestingly, these phosphorylation events are mediated by distinct subdomains
of IL-17RA (Figure 3A). Regulation of ERK and hence phosphorylation at Thr-188 is mediated
by the SEFIRTILL region.
43
. By contrast, regulation of GSK3 is mediated by the C-BAD
motif. In other systems PI3K signalling is upstream of GSK3, but standard PI3K inhibitors
have no effect on IL-17A signalling in this setting. Unexpectedly, the consequence of C/
EBP phosphorylation is to downregulate its transcriptional capacity, and so this pathway is
one of the few known inhibitory signalling events mediated by IL-17A
61
. Because induction,
alternative translation and phosphorylation of C/EBP all occur during a time frame in which
C/EBP is also upregulated by IL-17A
51
, there is a dynamic and complex interplay between
members of the C/EBP family that could allow for detailed transcriptional control of C/EBP-
dependent genes. Finally, C/EBP can be regulated by subcellular localization and association
with numerous transcription factors, which provides future avenues of investigation in the
context of IL-17R signalling
69
.
More broadly, these molecular events help to explain the synergism between IL-17 and other
cytokines, particularly TNF
71
. The mechanism underlying such synergy occurs partly through
enhanced effects on mRNA stability
38, 72
, but C/EBP transcription factors help to mediate
cooperative activation of target promoters. For example, TNF and IL-17A have an additive
effect on the induction of the Il6 promoter, and overexpression of either C/EBP or C/EBP
can replace the contribution of IL-17A to this cooperative signal
53
.
Other pathways activated by IL-17RA
Additional events have been implicated in IL-17RA signalling, although generally there is less
evidence for these other pathways. Pharmacological inhibitors of J anus kinases (J AKs) have
been reported to limit IL-17A signalling
73, 74
, but these results should be interpreted with
caution due to the non-specific effects of such compounds. Weak activation of signal transducer
and activator of transcription (STAT) factors has been reported, but secondary effects from
IL-17A-induced secretion of cytokines such as IL-6 were not ruled out satisfactorily
38
. PI3K
pathways have similarly been implicated, and IL-17A signalling in lung epithelial cells is
associated with increased lipid phosphorylation, weak AKT phosphorylation and inhibition by
specific PI3K inhibitors
73
. However there are few solid biochemical data indicating which
PI3K isoforms are involved in this process. Additionally, IL-17RA, and hence downstream
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signalling, might be controlled by inducible degradation. An overexpression study showed that
IL-17A triggers the ubiquitylation and degradation of IL-17RA, which might involve the E3
ubiquitin ligase TRAF6
75
.
Other receptors of the IL-17R family
IL-17RC
IL-17RC (also known as IL-17RL) was identified by homology searches of mammalian
expressed sequence tag (EST) databases. Complementation studies showed that IL-17RC is
required for IL-17A- and IL-17F-mediated signalling, although it is insufficient to signal
without IL-17RA. This study also revealed an unexpected species-dependent interaction
between IL-17R subunits. Specifically, mouse and human IL-17A show no species dependence
in signalling
13
, whereas mouse but not human IL-17RA can reconstitute IL-17A-dependent
signalling in murine Il17ra
-/-
fibroblasts. Furthermore, co-expression of human but not mouse
IL-17RC with human IL-17RA can restore signalling
35
. Consistently, fibroblasts from
Il17rc
-/-
mice fail to induce IL-6 or GM-CSF production in response to either IL-17A or IL-17F
76
. The reason for this species dependence is not clear, but could be important in evaluating
anti-cytokine therapeutics in pre-clinical models.
The findings discussed above argue that the IL-17A-binding complex is an obligate multimeric
receptor containing both IL-17RA and IL-17RC. However, these subunits have reciprocal
expression patterns, suggestive of tissue-dependent activities
21, 22
. In contrast to IL-17RA,
IL-17RC expression is low in haematopoietic tissues and high in non-immune cells of the
prostate, liver, kidney, thyroid and joints
21, 77
. In terms of biological signalling, it is
conceivable that differential expression of IL-17R subunits may provide an avenue for tissue-
specific signalling by IL-17A and/or IL-17F. Whereas IL-17RA binds with an extremely low
affinity to IL-17F, IL-17RC binds with higher affinity to IL-17F than to IL-17A
21
.
Accordingly, cells with high IL-17RC expression could be more responsive to IL-17F, whereas
those with low IL-17RC expression might respond better to IL-17A. Consistent with this idea,
studies in Il17a
-/-
and Il17f
-/-
mice indicated that IL-17A but not IL-17F mediates signals in
murine T cells, correlating with undetectable levels of IL-17RC
22
. This raises the intriguing
question of whether IL-17RA signals as a homo-multimer in T cells, or whether there is another
subunit that might pair with IL-17RA in certain cell types such as T cells. This information
can also be valuable therapeutically; soluble IL-17RA can efficiently block IL-17A-dependent
but not IL-17F-dependent responses, providing an avenue to selectively target individual
cytokines (Figure 2)
21
. Defining the precise nature of IL-17-binding complexes in different
tissues is thus important for understanding signalling but also in terms of how to optimally
target this system for clinical benefit.
With the exception of IL-17RA, other members of the IL-17R superfamily are highly spliced
at sites in the extracellular domain, potentially giving rise to both agonistic and antagonistic
(soluble) forms of the receptors. Indeed, more than 90 splice isoforms of IL-17RC were
identified in human prostate cancer lines
78
. In mice, only four splice variants of IL-17RC are
found in EST databases
21
. Interestingly, there is ligand preference of IL-17RC splice isoforms,
as certain forms bind preferentially to IL-17A or IL-17F; moreover, some isoforms do not bind
either cytokine, suggesting that there might be additional ligands for this receptor subunit
21
.
The mechanism by which splicing is controlled has not been determined, but may be important
for directing the ability of a particular cell or tissue to respond to different IL-17 family
cytokines.
As expected, the IL-17RC cytoplasmic tail is required for signal transduction
35
, but not for
inducible co-immunoprecipitation with IL-17RA (W. Ouyang, personal communication). So
far, little is known about exactly how IL-17RC participates in signalling. IL-17RC contains a
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SEFIR but not an obvious TILL domain, and it is not known whether IL-17RC binds directly
to ACT1, TRAF6 or other downstream signalling molecules. It is tempting to speculate that
IL-17RC might recruit unique molecules to the receptor complex, but it is possible that
IL-17RC simply increases the number of ACT1 molecules within the complex to facilitate
more efficient signal transduction.
IL-17RB
IL-17RB (also known as IL-25R, Evi-27 or IL-17rh-l) binds both IL-17B and IL-17E/IL-25.
This subunit is expressed by various endocrine tissues as well as kidney, liver and T
H
2 cells
79
. IL-17RB is also highly spliced in the extracellular domain
80
, although no evaluation of the
role of each splice variant has been reported. Recent evidence indicates that IL-17RB pairs
with IL-17RA to form a functional IL-25R complex, but the specific contribution of each
subunit to downstream signalling is unclear
27
. This finding raises issues regarding conclusions
drawn from studies of Il17ra
-/-
mice, as effects attributed to IL-17A and IL-17F could involve
additional contributions from IL-25. Unlike IL-17RA, IL-17RB encodes a TRAF6-binding
motif in its cytoplasmic tail. Indeed, antibody-mediated crosslinking of the receptor activates
NF-B, which can be blocked by a dominant-negative form of TRAF6 but not TRAF2
81
. IL-25
has been shown to activate NFATc1 and J UNB, leading to increased IL-4 expression by T
H
2
cells
82
. Like the rest of the family, the IL-17RB cytoplasmic tail contains a SEFIR domain,
and was recently shown to bind ACT1 in a SEFIR-dependent manner. Accordingly, Act1
-/-
mice show deficits in responding to IL-25 in vivo
26, 83
.
IL-17RD
IL-17RD has no known ligand (Fig. 1). It was first identified in zebrafish (Danio rerio) based
on a similar expression pattern to the fibroblast growth factor receptor (FGFR), and thus is
commonly known as SEF (similar expression to the FGF receptor). IL-17RD seems to be the
most evolutionarily ancient member of the IL-17R family, as it has homologues in sea lamprey,
frogs and C. elegans
84
. Its role in zebrafish suggests that the original function of the IL-17R
family may have been to control development. Interestingly, this represents another parallel to
the TLR family, as Drosophila Toll acts to control dorsoventral polarity during embryonic
development. IL-17RD inhibits FGF-mediated RASMAPK and PI3K signalling in both
zebrafish and Xenopus laevis development
85
. IL-17RD blocks FGF in part by physically
associating with FGFR1 and FGFR2. The cytoplasmic tail of IL-17RD is required for its ability
to inhibit signalling and associate with FGFR, but the extracellular domain is dispensable
85
.
The human homologue of IL-17RD also co-immunoprecipitates with FGFR1 and can inhibit
FGF-dependent ERK activation and FGF-dependent proliferation
86-88
. Although the
mechanism by which IL-17RD-mediated inhibition occurs is not defined, murine IL-17RD has
been shown to interact with TAK1 to activate the MKK4J NK pathway
89
. In addition to
associating with FGFR, human IL-17RD has been shown to form homodimers, although it is
not clear whether these are functional
86
. IL-17RD can also interact with IL-17RA, although
the biological significance of this association remains unclear
36
. IL-17RD-deficient mice are
viable and have no obvious developmental abnormalities, but detailed phenotypic analysis has
not yet been carried out (J . Tocker, personal communication).
IL-17RE
IL-17RE is the least understood member of the IL-17R family, but recent studies suggest that
its ligand is IL-17C (S. Levin, personal communication). IL-17RE is highly spliced, with six
isoforms identified in EST databases. Ectopic expression of an EPORIL-17RE construct in
the myeloid BaF3 cell line indicated that this receptor might promote proliferation, but this
occurred in a ligand-independent manner, which raises concerns about the validity of the assay
system
90
.
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Perspectives and implications
The past decade has seen great success in exploiting cytokines for therapeutic intervention.
For example, antibodies or soluble receptors that neutralize TNF have revolutionized the
treatment of autoimmune disease
91
. Therapies that target IL-12, IL-23, IL-6 and IL-1 have
also had success in the clinic or experimental trials, and all of these cytokines affect the T
H
17
cell pathway (as well as other T
H
17-like cells that produce IL-17A and related ligands). The
roles of IL-17-family cytokines in autoimmunity make this system an obvious target for clinical
intervention
92
. Strategies include administering neutralizing antibodies specific for IL-17A,
IL-17F and/or IL-17A-IL-17F, or for IL-17RA or IL-17RC. Soluble receptors or PLAD
peptides could also be used to block ligandreceptor interactions
21, 50
(Figure 2).
Understanding which receptor subunit(s) to target while avoiding deleterious effects on host
immunity will be key for developing effective treatments. In this regard, the varying affinity
of each IL-17R subunit for its ligand could be exploited to allow more selective inhibition; for
example, soluble IL-17RA reagents selectively block IL-17A, whereas soluble IL-17RC blocks
both IL-17A and IL-17F
21
. In exciting new developments, IL-17A-specific antibodies have
shown promise in early trials for the treatment of psoriasis (D. Patel, personal communication).
Although current anti-cytokine strategies target ligands or extracellular features of cytokine
receptors, defining the downstream signal transduction mechanisms might also allow for small
molecule inhibitors that block specific intracellular pathways.
In summary, IL-17 came to prominence as the signature cytokine of the new T
H
17 subset of
T cells, and its unusual structure, receptor and proximal signalling pathways have presented
new paradigms in cytokine biology. However, there are still many open questions pertaining
to ligandreceptor relationships, molecular signalling events, and functions in vivo (Box 2).
The next few years will certainly see important new insights about this fascinating family of
cytokines.
Box 1
IL-17R signalling is a bridge between adaptive and innate immunity
Traditional TH1 and TH2 signature cytokines signal through J AK-STAT-mediated
pathways, with IFN activating a J AK1/2-STAT1-dependent pathway and IL-4 activating
a J AK1/3- STAT6-dependent pathway. Activation of these pathways is critical both for the
effector functions of these cells but also for their development. In contrast, IL-17A and
IL-17F derived from TH17 cells promote ACT1/TRAF6/NF-B-dependent signalling,
which is much more reminiscent of receptors associated with innate immunity, such as IL-1-
family receptors and TLR ligands. Interestingly, another TH17 hallmark cytokine is IL-22,
which activates a J AK-STAT3 signalling programme, but the downstream gene targets are
strikingly similar to genes induced by IL-17. Thus, TH17 cells promote signals typical of
early inflammatory events, and in this sense serve to bridge innate and adaptive immune
processes.
Box 2
Future avenues of investigation in the IL-17R signalling field
There remain many unanswered questions with regards to IL-17R signalling. To start, not
all of the ligandreceptor relationships are defined. For example, the receptor for IL-17D
is unknown, as is the ligand(s) for IL-17RD (see also Figure 1). The stoichiometry of the
various receptor complexes are not well delineated, nor is there substantial information on
how expression of each receptor subunit is controlled; for example, why are IL-17RA and
IL-17RC reciprocally expressed if they form a heteromeric complex? Is there tissue
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specificity in terms of IL-17R composition, and if so, does this translate into differential
signalling? Does IL-17RC have another ligand? In the receptor complex for IL-17A, IL-17F
and IL-17A-IL-17F, the molecular contribution of the IL-17RC cytoplasmic tail is
unknown, and a similar question exists for the IL-25R/IL-17RB subunit when paired with
IL-17RA. The details of the NF-B pathway are not fully elucidated; for example, a possible
role for I is intriguing but undetermined. It is not known whether ACT1 binds to
additional signalling molecules or kinases that might be parallel to IRAKs in the TLR
system. The signalling pathway(s) leading to C/EBP activation are incompletely elucidated.
How does IL-17 control mRNA transcript stability? The role of IL-17 signalling in T and
B cells is also not well understood. What is the contribution of IL-17R signalling pathways
in vivo? What is the significance of a virally encoded IL-17A homologue in Herpesvirus
saimiri? Doubtless, future investigations will address these and other important questions.
On-line summary
The cytokine IL-17 came into the limelight with the discovery of T helper 17
(T
H
17) cells, a new CD4
+
T cell subset that represents the first main revision of
the T
H
1-T
H
2 cell paradigm in two decades. IL-17 and its receptor are founding
members of a new family of cytokines (IL-17A-F) and receptors (IL-17RA-RE)
with unique structures and signalling properties.
Although they are produced by different cell types, all IL-17-family cytokines
seem to promote inflammation, both in host defence and in inflammatory
pathology.
IL-17RA, a receptor for IL-17A and IL-17F, is the founding member of the IL-17R
extended family and seems to function as a co-receptor with at least 2 other
members of the IL-17-ligand family. IL-17RA is expressed ubiquitously as a pre-
associated multimeric receptor, but is also dynamically regulated in certain cell
types.
IL-17RA has the largest cytoplasmic tail of the family, which potentially provides
docking sites for numerous signalling intermediates. Acting through a SEFIR
subdomain that is conserved between but also unique to the IL-17R extended
family, IL-17RA engages the ACT1 adaptor to induce the NF-B, MAPK and C/
EBP pathways.
IL-17RC is a co-receptor with IL-17RA for IL-17A and IL-17F signalling, and
IL-17RB/25R associates with IL-17RA to mediate IL-17E/25 signalling. Far less
is known about how these other receptors activate downstream signalling
pathways.
Efforts to target IL-17 family cytokines, particularly IL-17A and IL-17RA, are
underway for the treatment of autoimmune diseases. Understanding the molecular
features of this family may provide useful information.
Acknowledgments
I thank J . Tocker (Amgen, Seattle WA), S. Levin (Zymogenetics, Seattle WA), W. Ouyang (Genentech, South San
Francisco CA), L. Li (Virginia Polytechnic University, Blacksburg VA), T. Hamilton (Cleveland Clinic, Cleveland
OH) and D. Patel (Novartis, Basel, Switzerland) for sharing unpublished information. I thank D. Ascherman, R. Onishi
(University of Pittsburgh, Pittsburgh PA), S. Khader (Childrens Hospital of Pittsburgh, Pittsburgh PA), F. Shen
(Genentech, South San Francisco CA) and C. Dong (MD Anderson Cancer Center, Houston TX) for critical reading.
S.L.G. was supported by the National Institutes of Health, USA (AR054389, DE018822).
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Glossary
T
H
1 and T
H
2 cells There are two main subsets of activated CD4
+
T cells: T
H
1 cells and
T
H
2 cells. T
H
1 cells produce interferon-

and tumour-necrosis factor,

thereby promoting cell-mediated immunity, primarily directed towards
intracellular pathogens. T
H
2 cells produce interleukin-4 (IL-4), IL-5 and
IL-13, thereby supporting humoral immunity and counteracting T
H
1-
cell responses.
T
H
17 cells A newly-described subset of activated CD4+T cells, characterized by
production of IL-17(A), IL-17F, IL-22, IL-21 and (in humans) IL-26.
These cells promote neutrophil activation and immunity to extracellular
pathogens. TH17 cells also promote inflammation in autoimmunity.
T cell A T cell that expresses a T-cell receptor consisting of a -chain and a
-chain. These T cells are present mainly in the intestinal epithelium as
intraepithelial lymphocytes (IELs). Although the exact function of T
cells (or IELs) is still unknown, it has been suggested that mucosal T
cells are involved in innate immune responses by the mucosal immune
system.
Lymphoid tissue
inducer (LTi) cell
A cell that is present in developing lymph nodes, Peyers patches and
nasopharynx-associated lymphoid tissue (NALT). Lymphoid-tissue
inducer cells are required for the development of these lymphoid organs.
The inductive capacity of these cells for the generation of Peyers
patches and NALT has been shown by adoptive transfer, and it is
generally assumed that they have a similar function in the formation of
lymph nodes.
Collagen-induced
arthritis (CIA)
An experimental model of rheumatoid arthritis. Arthritis is induced by
immunization of susceptible animals with type II collagen.
Fluorescence
resonance energy
transfer (FRET)
A technique that is used to measure protein-protein interactions either
by microscopy or flow cytometry. Proteins fused to cyan, yellow or red
fluorescent proteins are expressed and assessed for interaction by
measuring the energy transfer between fluorophores. Such transfer can
only occur if proteins physically interact.
Classical NF-B
pathway
A typical pathway of NF-B activation that involves phosphorylation
and degradation of the prototypical NFB inhibitor, IB.
Non-classical
NF-B pathway
A pathway of NFB activation that does not involve IB.degradation
but relies on the processing of an NFB precursor protein, p1OO,
leading to nuclear translocation of the p52RELB NFB heterodimer.
Toll/IL-1 receptor
(TIR) domain
An intracellular-signalling domain that is found in IL-1 receptors, Toll-
like receptors and several adaptor proteins, including MYD88 (myeloid
differentiation primary-response protein 88).
BB-loop A structured loop linking the second -helix and the second -sheet
within TIR domains. This loop is a specificity determinant for TIR
domains, and certain mutations in the BB-loop cause impairment of
TLR signalling.
Exosome
complex
A multi-protein complex that degrades various forms of RNA. Certain
mRNA transcripts (particularly those encoding cytokines and
chemokines) are inherently unstable due to the presence of Au-rich
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elements (AREs) located within the 3 untranslated region. Proteins that
bind to AREs target these transcripts to exosomes for degradation.
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Figure 1. IL-17 receptor family ligand-receptor relationships and main structural features
So far, five members of the IL-17 receptor superfamily have been identified, as indicated in
Table 1. The various receptor complexes that correspond to each ligand are indicated, although
it should be emphasized that in no instance has the stoichiometry been demonstrated
definitively. The receptor for IL-17D is unknown, as is the ligand(s) for IL-17RD/SEF or an
IL-17RA/IL-17RD pairing if it exists (see Ref
75
). FN, fibronectin III-like domain; SEFIR,
SEF/IL-17R-related signalling domain; TILL, TIR-like loop; CBAD, C/EBP activation
domain.
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Figure 2. IL-17R binding complex and strategies for blockade
The IL-17R complex contains an undetermined number of IL-17RA and IL-17RC subunits,
although studies so far indicate that it might be at minumum trimeric, which is the form shown
here. Both IL-17A and IL-17F signal through these subunits, although IL-17A has far higher
affinity for IL-17RA than for IL-17RC, whereas IL-17F has a somewhat greater affinity for
IL-17RC than for IL-17RA
21
. There are multiple anti-cytokine strategies proposed designed
to block signalling through the IL-17 receptor
92
. Antibodies specific for individual ligands or
the individual receptor subunits represent the most straightforward approach. Additionally,
soluble IL-17R subunits such as fusions to IgG-Fc have been evaluated in pre-clinical models
(reviewed in Ref.
93
). Finally, preventing receptor assembly by means of soluble PLAD
peptides is another possible avenue for drug development, analogous to approaches used with
TNFR signalling
47,50
.
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Figure 3. A. Schematic diagram of IL-17 signalling
The IL-17R complex is composed of IL-17RA and IL-17RC. Both subunits encode SEFIR
domains
59
, but a sequence similar to the TIR BB-loop is found only on IL-17RA, termed a
TIR-like loop (TILL)
43
. IL-17RA engages the SEFIR-containing ACT1 adaptor to mediate a
variety of downstream events
62
. Specifically, ACT1 is required for recruitment of TRAF6
(and possibly TRAF3), which is an essential upstream activator of the classical NF-B
pathway. It is not clear whether TRAF6 is also required for MAPK activation. Act1
-/-
cells fail
to upregulate C/EBP (LAP and LAP* splice variants) and C/EBP as well, another event that
might be downstream of NF-B
58, 63
. ACT1, but not TRAF6, is required for IL-17A-induced
stabilization of several target mRNAs, particularly those encoding chemokines and cytokines
Gaffen Page 21
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. Interestingly, ERK might also be controlled, at least indirectly, by ACT1-independent
pathways, as Act1
-/-
cells show strong upregulation of ERK phosphorylation 24 hours after
IL-17A stimulation
63
. ERK mediates rapid phosphorylation of C/EBP on Thr-188
61
. A
second functional domain on IL-17RA is located in the C-terminal region, and is not required
for efficient activation of NF-B or the MAPK pathways. However, deletion of this domain
results in impaired alternative translation of C/EBP from the LAP isoform to the LAP*
isoform
43
, and hence was termed the C/EBP-activation domain (CBAD). The CBAD is
also required for IL-17A-mediated inducible phosphorylation of C/EBP on Thr-179, which
is mediated by GSK3
61
. B. Comparison of IL-17R and TLR/IL-1R signalling. IL-17R
and TLR/IL-1R signalling differ in functional receptor motifs (SEFIR/TILL versus TIR) and
proximal adaptors (ACT1 versus MYD88 and TRIF), but converge on common pathways (NF-
B, C/EBP and MAPK). Hence these receptors activate similar, although not identical, panels
of downstream genes.
Gaffen Page 22
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Timeline. Major events in the history of the IL-17/Th17 field
References in:
11213469495, 96597, 97552, 9899, 100101-10310458, 6310535106-10810922
Gaffen Page 23
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Gaffen Page 24
Table 1
Extended IL-17/IL-17R family, expression and known functions
Other
common
names
Receptor(s) Main functions Expression
IL-17 IL-17A,
CTLA-8
IL-17RA
IL-17RC
Autoimmune pathology,
Neutrophil recruitment,
immunity to
extracellular pathogens
Th17, CD8 cells, -
TCR+T cells, NK,
NKT, LTi
IL-17B IL-17RB Pro-inflammatory
activities?
GI tract, pancreas,
neurons
IL-17C IL-17RE Pro-inflammatory
activities?
Prostate, fetal kidney
IL-17D ? Pro-inflammatory
activities?
Muscle, brain heart
lung, pancreas,
adpose tissue
IL-17E IL-25 IL-17RB
IL-17RA
Induce Th2, suppress
Th17
Intraepithelial
lymphocytes, lung
epithelial cells,
alveolar
macrophages,
eosinophils,
basophils, NKT cells,
Th2 cells, mast cells,
GI tract, uterus
IL-17F IL-17RA
IL-17RC
Neutrophil recruitment,
immunity to
extracellular pathogens
Th17, CD8 cells, -
TCR+T cells, NK,
NKT, LTi
IL-17A/F IL-17RA
IL-17RC
Autoimmune pathology
(presumed), Neutrophil
recruitment, immunity to
extracellular pathogens
Th17, CD8 cells, -
TCR+T cells, NK,
NKT, LTi
vIL-17 ORF13 IL-17RA
IL-17RC?
unknown Herpesvirus saimiri
Nat Rev Immunol. Author manuscript; available in PMC 2010 August 1.