REVIEWS

Structure and signalling in the IL17 receptor family

Sarah L. Gaffen

Abstract | Interleukin17A (IL17A), the hallmark cytokine of the newly defined T helper 17 (Th17) cell subset, has important roles in protecting the host against extracellular pathogens, but also promotes inflammatory pathology in autoimmune disease. IL17A and its receptor (IL17RA) are the founding members of a newly described family of cytokines and receptors that have unique structural features which distinguish them from other cytokine families. Research defining the signal transduction pathways induced by IL17R family cytokines has lagged behind that of other cytokine families, but studies in the past 2 years have begun to delineate unusual functional motifs and new proximal signalling mediators used by the IL17R family to mediate downstream events.
TH1 and TH2 cells

The two main subsets of activated CD4+ T cells. T helper 1 (Th1) cells produce interferon and tumour necrosis factor, thereby promoting cellmediated immunity that is mainly directed towards intracellular pathogens. Th2 cells produce interleukin4 (IL4), IL5 and IL13, thereby supporting humoral immunity and counteracting Th1 cell responses.

TH17 cell

A cell belonging to a newly described subset of activated CD4+ T cells that is characterized by the production of interleukin17A (IL17A), IL17f, IL22, IL21 and (in humans) IL26. T helper 17 (Th17) cells promote neutrophil activation and immunity to extracellular pathogens. They also promote inflammation in autoimmunity. University of Pittsburgh, Department of Medicine, Division of Rheumatology and Clinical Immunology, Pittsburgh, Pennsylvania 15261, USA. email: sig65@pitt.edu doi:10.1038/nri2586 Published online 3 July 2009

In 1986, a seminal paper by Coffman, Mosmann and colleagues postulated the existence of subsets of T helper (Th) cells characterized by the secretion of distinct cytokines, which were designated Th1 and Th2 cells1. Although this paradigm dominated for nearly 2 dec ades2, discrepancies arose as details of Th cell develop ment became more refined. In particular, deficiency in interleukin12 (IL12) (specifically, the IL12p40 subunit of this heterodimeric cytokine), which drives the devel opment of the Th1 cell lineage, frequently failed to phe nocopy deficiency in interferon (IFN), the hallmark Th1type cytokine3. The basis for this paradox became evident when it was recognized that IL12p40 is also a component of IL23 (together with IL23p19), and so IL12p40deficient mice lack both IL12 and IL23 (ref. 4). Further studies showed that IL23 stimulates the production of IL17A by a subset of CD4+ T cells5,6, and IL23p19deficient mice, but not IL12p35deficient mice, are susceptible to certain autoimmune diseases7. This revealed a new branch of the Th cell family tree, now known as Th17 cells (TIMeLINe). Numerous reports rapidly followed describing the factors involved in the differentiation of this lineage, the additional cytokines produced by T h17 cells and the production of Th17type cytokines by other cell subsets. To summarize briefly, Th17 cell differentia tion is regulated by the transcription factors signal transducer and activator of transcription 3 (STAT3), retinoic acid receptorrelated orphan receptort (RORt) and aryl hydrocarbon receptor, and is driven by transforming growth factor (TGF), IL1 and IL6; IL23 is required to expand and stabilize the cell

population. In addition to IL17A, Th17 cells produce IL17F (discussed below), IL21, IL22 and IL26, as well as chemokines such as CCchemokine ligand 20 (CCL20; also known as MIP3). Th17 cells function prominently at mucosal surfaces and trigger pro inflammatory danger signals that promote neutrophil mobilization and the expression of antimicrobial factors. Furthermore, T h17 cells drive inflamma tory pathology in various autoimmune conditions. Various Th17like cells that produce a similar range of cytokines to T h17 cells also exist; these include T cells , natural killer (NK) cells, NKT cells and lymphoid tissue inducer (LTi) cells. The reader is referred to several excellent reviews on this topic810. Less attention has been paid to the mechanisms by which IL17 family cytokines mediate effects at a molecular level. IL17A and its receptor (IL17RA) are founding members of a newly described family of cytokines (IL17AIL17F) and receptors, known as the IL17R family (IL17RAIL17RE) (TABLe 1). Receptors belonging to the IL17R family have unique structural features and mediate signalling events that are surpris ingly distinct from those triggered by other cytokine receptors, particularly those usually involved in adap tive immunity. The signature cytokines involved in the Th1 and Th2 cell responses trigger Janus kinase (JAK) STAT signalling pathways, whereas IL17R family cytokines mediate signalling through a distinct pathway that depends on ACT1 (also known as CIKS), culmi nating in the activation of proinflammatory media tors that are usually associated with innate immune signalling, such as nuclear factorB (NFB) (BOX 1).
www.nature.com/reviews/immunol

556 | AuGuST 2009 | VOLuME 9 2009 Macmillan Publishers Limited. All rights reserved

REVIEWS
Timeline | Important events in the history of the IL17 and TH17 cell field
First demonstration that Th17 cells are pathogenic in autoimmunity99 Th17 cells are shown to arise as a separate lineage from Th1 and Th2 cells52,98 Expression of IL23R is linked to the development of human Crohns disease100 RORt and STAT3 are shown to drive Th17 cell differentiation104 TGF and IL6 are shown to drive Th17 cell development; TReg cells are shown to arise in opposition to Th17 cells101103 Patients with hIES are shown to be selectively deficient in Th17 cells owing to mutations in STAT3 (ref. 109)

IL17 is shown to drive joint destruction in mouse models of rheumatoid arthritis95,96 Il17ra/ mice are generated and are shown to be susceptible to infection with Klebsiella pneumoniae94

CTLA8, later renamed IL17A, is cloned12

IL17RA is cloned13

1986

1993

1995

2000

2001

2003

2005

2006

2007

2008

2009

Mosmann, Coffman and colleagues propose the Th1Th2 cell paradigm1

Borrelia burdorferistimulated APCs are shown to trigger T cells to secrete IL17 but not IFN or IL4 (ref. 6) IL23 is cloned and IL23 is found to share a p40 subunit with IL12 (ref. 4)

Il23p19/, but not Il12p35/, mice are shown to be resistant to CIA and EAE7,97 SEFIR domain is defined59 IL23 is shown to stimulate CD4+ T cells to produce IL17 (ref. 5)

ACT1 is shown to be a key downstream mediator of IL17 induced signalling 58,63 Th17 cells are shown to produce IL22 (ref. 105)

IL17RC is found to be the coreceptor for IL17A and IL17F35 Th17 cells are shown to produce IL21
(refs 106108)

Direct comparison of the phenotype of Il17a/ and Il17f/ mice22 IL17specific antibodies show efficacy in early clinical trials for the treatment of psoriasis (D. Patel, unpublished observations)

APC, antigenpresenting cell; CIA, collageninduced arthritis; CTLA8, cytotoxic T lymphocyte antigen 8; EAE, experimental autoimmune encephalomyelitis; hIES, hyper IgE syndrome; IFN, interferon; IL, interleukin; IL17R, IL17 receptor; RORt, retinoic acid receptorrelated orphan receptort; SEFIR, SEF/IL17R; STAT3, signal transducer and activator of transcription 3; TGF, transforming growth factor; Th cell, T helper cell; TReg cell, regulatory T cell.

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 mediated by the mucosal immune system.

So, by virtue of the unusual signalling properties of IL17, T h17 cells act as a bridge between adaptive and innate immunity 11. Recent work has begun to define the architecture of the IL17R family and its sometimes surprising ligandreceptor relationships and signal transduction pathways. This Review dis cusses recent discoveries in this field in the context of cytokine receptor biology and highlights the poten tial implications of this knowledge with respect to emerging therapeutics.

and Caenorhabditis elegans, among others16. Although the cellular sources and expression patterns of the vari ous mammalian IL17 family members are different (TABLe 1), they all have proinflammatory activities. IL17A and IL17F drive inflammation and auto immunity. IL17A and IL17F are by far the best char acterized cytokines of the IL17 cytokine family. Both are covalent homodimers, and recent findings show that they also form IL17AIL17F heterodimers17,18 (fIG. 1) . IL17AIL17F heterodimers are produced at higher levels than IL17A homodimers by human peripheral blood mononuclear cells in vitro 17, but the form that predominates in vivo is not well defined19. IL17A, IL17F and the IL17AIL17F heterodimer signal through the same receptor subunits, IL17RA and IL17RC (also known as IL17RL), which together form a heteromeric complex 20,21. however, IL17A and IL17F have distinct biological effects. Studies compar ing Il17a/ mice with Il17f/ mice indicate that IL17A has a more important role in driving autoimmunity than IL17F, probably owing to its more potent strength of signalling 19,22. The role of the IL17A IL17F heterodimer in vivo will be more challenging to evaluate. The basis for functional differences between IL17A and IL17F could be the markedly decreased strength of signalling triggered by IL17F compared with IL17A, as IL17Finduced responses are 1030 fold weaker in terms of downstream gene activation than those of IL17A, with IL17AIL17F hetero dimers acting at an intermediate level17,23,24. The precise nature of their respective receptor complexes has not been defined (discussed further below). As IL17RA
VOLuME 9 | AuGuST 2009 | 557

Lymphoid tissue inducer (LTi) cell

A cell that is present in developing lymph nodes, Peyers patches and nasopharynxassociated lymphoid tissue (NALT). LTi 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.

IL17 cytokines constitute a unique family IL17A was identified by a subtractive hybridization screen in a rodent T cell library 12 (TIMeLINe), but was not immediately recognized as a cytokine owing to its unusual amino acid sequence. Subsequent characteri zation showed that IL17A is produced by T cells and stimulates the production of factors such as granulo cyte colonystimulating factor (GCSF), IL6 and IL8, indicating that it should be considered a bona fide cytokine13,14. Intriguingly, the amino acid sequence of IL17A is 58% identical to an open reading frame in Herpesvirus saimiri, a T celltropic gammaherpes virus13, although the importance of homology to this viral protein (known as vIL17) remains unknown. Genomic sequencing efforts led to the identification of several putative IL17A homologues: IL17B, IL17C, IL17D, IL17E (also known as IL25) and IL17F. The only member of the family to have been crystal lized for structural studies is IL17F, which adopts a threedimensional cysteineknot fold architecture15. IL17 family homologues have been found in various species, including sea lamprey, rainbow trout, zebrafish

NATuRE REVIEwS | Immunology 2009 Macmillan Publishers Limited. All rights reserved

REVIEWS
Collageninduced arthritis
An experimental model of rheumatoid arthritis. Arthritis is induced by the immunization of susceptible animals with type II collagen.

Table 1 | Expression and known functions of members of the extended IL17 receptor family
Family member
IL17A

other common Receptors names

IL17 and CTLA8 IL17RA and IL17RC

main functions
Autoimmune pathology, neutrophil recruitment and immunity to extracellular pathogens Proinflammatory activities? Proinflammatory activities? Proinflammatory activities? Induces Th2 cell responses and suppresses Th17 cell responses

Expression
Th17 cells, CD8+ T cells, T cells, NK cells, NKT cells and LTi cells

IL17B IL17C IL17D IL17E

NA NA NA IL25

IL17RB IL17RE Unknown IL17RA and IL17RB

Cells of the gastrointestinal tract, pancreas and neurons Cells of the prostate and fetal kidney Cells of the muscles, brain, heart, lung, pancreas and adipose tissue Intraepithelial lymphocytes, lung epithelial cells, alveolar macrophages, eosinophils, basophils, NKT cells, Th2 cells, mast cells, and cells of the gastrointestinal tract and uterus Th17 cells, CD8+ T cells, T cells, NK cells, NKT cells and LTi cells Th17 cells, CD8+ T cells, T cells, NK cells, NKT cells and LTi cells

IL17F

NA

IL17RA and IL17RC IL17RA and IL17RC

Neutrophil recruitment and immunity to extracellular pathogens Autoimmune pathology (presumed), neutrophil recruitment and immunity to extracellular pathogens

IL17AIL17F heterodimer

NA

vIL17

ORF13

IL17RA (and Unknown IL17RC?)

Herpesvirus saimiri

CTLA8, cytotoxic T lymphocyte antigen 8; IL17R, interleukin17 receptor; LTi, lymphoid tissue inducer; NA, not applicable; NKT, natural killer T; ORF13, open reading frame 13; Th, T helper.

and IL17RC have different affinities for IL17A and IL17F, it is plausible that different receptor complexes exist with varying ratios of IL17RA and IL17RC that have different ligand preferences. IL17E is a Th2 cellpromoting cytokine. IL17E is pro duced by mucosal epithelial cells and many immune cell types (TABLe 1). Transgenic overexpression of IL17E promotes eosinophilia and stimulates the production of Th2type cytokines. Moreover, IL17E limits Th17 cell development by inducing the expression of IL13 by dendritic cells (DCs) or by inhibiting IL23 production by macrophages (reviewed in ref. 25). IL17E binds a receptor complex composed of IL17RB (also known
Box 1 | IL17R signalling is a bridge between innate and adaptive immunity
Traditional T helper 1 (TH1) and TH2 cell signature cytokines induce the activation of signalling pathways mediated by Janus kinase (JAK) and signal transducer and activator of transcription (STAT) proteins, with the TH1-type cytokine interferon- (IFN) activating a JAK1 and JAK2STAT1-dependent pathway and the TH2-type cytokine interleukin-4 (IL-4) activating a JAK1 and JAK3STAT6-dependent pathway. Activation of these pathways is crucial both for the effector functions of these cells and for their development. By contrast, IL-17A and IL-17F produced by TH17 cells induce signalling mediated by ACT1 (also known as CIKS), TNFR-associated factor 6 (TRAF6) and nuclear factor-B, which is much more reminiscent of receptors associated with innate immunity, such as IL-1 family receptors and Toll-like receptors. Interestingly, another TH17 cell signature cytokine is IL-22, which activates a JAK1 and TYK2STAT3 signalling pathway, but the downstream gene targets of which are markedly similar to the genes induced by IL-17. So, TH17 cells promote signals that are typical of early inflammatory events and in this sense serve to bridge innate and adaptive immune responses.

as IL25R) and IL17RA26 (fIG. 1). Il17rb/ and Il17ra/ mice fail to respond to IL17E, and both knockout strains are refractory to pulmonary inflammation induced by intranasal application of IL17E27. Taken together, these observations indicate that there is intriguing crosstalk between members of the IL17 cytokine family. IL17B, IL17C and IL17D functions are poorly defined. IL17B, IL17C and IL17D remain poorly character ized. IL17B binds to IL17RB with fairly high affin ity 28, and IL17C was recently reported to bind IL17RE and to activate NFB (S. Levin, personal communica tion). The receptor (or receptors) for IL17D remains unknown. Ectopic expression of IL17B and IL17C by CD4+ T cells exacerbates collageninduced arthritis (CIA)29, and intranasal administration of adenoviruses expressing IL17C, IL17A or IL17F triggers comparable responses by neutrophils30, suggesting that these cytokines medi ate common biological effects, probably through shared signalling pathways. Antibodies specific for IL17B also partially suppress CIA29. IL17B and IL17C stimulate the transcription of an array of proinflammatory genes similar to those induced by IL17A and IL17F29,31. IL17D was reported to promote a proinflammatory gene expression profile in endothelial cells and to have a mild inhibitory effect on the proliferation of myeloid progenitor cells in vitro32. As more knockout mice are generated and the target receptors for IL17B, IL17C and IL17D become more clearly defined, we will gain an improved understanding of these newly described IL17 family members.
www.nature.com/reviews/immunol

558 | AuGuST 2009 | VOLuME 9 2009 Macmillan Publishers Limited. All rights reserved

REVIEWS
The IL17R family The IL17R family comprises five receptor subunits, IL17RAIL17RE 33 (fIG. 1) . Despite considerable sequence divergence, many of the genes encoding the IL17R family members are linked, with clusters on human chromosome 3 (for IL17RB, IL17RC, IL17RD and IL17RE) and mouse chromosomes 6 (for IL17RA, IL17RC and IL17RE) and 14 (for IL17RB and IL17RD). All of the receptor subunits are single trans membrane domaincontaining proteins, ranging in size from 499 to 866 amino acids (with smaller alternatively spliced forms also found, as discussed below). These receptor subunits contain certain conserved structural motifs, including an extracellular fibronectin IIIlike domain and a cytoplasmic SEF/IL17R (SEFIR) domain (see below). Although it is still not clear precisely how IL17R subunits interact to form productive receptor complexes, it is becoming evident that IL17RA, which is by far the largest member of the family, is a common signalling subunit used by at least four ligands.
IL17RA: expression and complex formation. IL17RA was initially identified as the receptor for mamma lian IL17A and vIL17 (ref. 13). IL17RA also binds IL17F, albeit weakly in humans, and is necessary for signal transduction mediated by IL17A, IL17AIL17F and IL17F15. Early studies showed that the affinity of IL17RA for IL17A 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, IL17RA pairs with IL17RC to induce responses to IL17A and IL17F35. Similarly, Il17ra/ mice are refractory to the effects of IL17E, suggesting that IL17RA is also a component of this receptor complex 27. Moreover, IL17RA might associate with IL17RD, as these subunits colocalize, and overexpression of a mutant form of IL17RD lacking a cytoplasmic tail inhibits IL17Adependent signals36. however, this finding has yet to be validated, and no
IL-17A IL-17A IL-17F

ligand has been identified for an IL17RAIL17RD receptor complex (fIG. 1). As it is used by many cytokines, IL17RA could be analogous to shared cytokine recep tor subunits, such as gp130, which is a common signal transducer for molecules of the IL6 family 37. IL17RA is expressed ubiquitously, with particu larly high levels in haematopoietic tissues 13,22. This expression pattern is interesting, as the main responses to IL17A occur in epithelial cells, endothelial cells and fibroblasts, although macrophages and DCs are also responsive (reviewed in ref. 38). Only a limited number of IL17Ainduced genes has been docu mented in lymphocytes, and these genes are distinct from those induced by IL17A in other cell types22,39. Although its expression is widespread, IL17RA can be dynamically regulated; for example, IL15 and IL21 upregulate the expression of IL17RA by CD8+ T cells40,41, and phosphoinositide 3kinase (PI3K) limits the expression of IL17RA by T cells. This could be biologically important, as IL17Ainduced signalling strength correlates with cell surface expression levels of IL17RA; in contrast to most cytokine receptors, high levels of IL17RA seem to be required for effective responses to IL17A42,43. Another function of IL17RA might be to limit signalling by receptormediated internalization of the ligand. Indeed, surface expression of IL17RA rapidly decreases after IL17A binding, theoretically internalizing IL17A and clearing it from the inflammatory milieu41. The composition of IL17RAcontaining receptor complexes is poorly defined. The textbook paradigm of cytokine receptor signalling is that individual receptor subunits reside in the membrane as monomers. Ligand binding promotes subunit oligomerization, thereby juxtaposing receptorassociated signalling intermedi ates such as kinases or adaptors. Inconsistent with this view are studies showing that many receptors actu ally exist as preassociated, multisubunit complexes (such as Tolllike receptors (TLRs), tumour necrosis

IL-17F

IL-17E

IL-17B

IL-17C

IL-17D

Unknown ligand

Unknown ligand

FN1 FN2 IL-17A

SEFIR TILL CBAD IL-17RC IL-17RA IL-17RB IL-17RA IL-17RB IL-17RE Unknown receptor IL-17RD IL-17RD IL-17RA

Figure 1 | Il-17R family ligandreceptor relationships and main structural features. So far, six interleukin17 (IL17) family cytokines (IL17AIL17F) and five members of the IL17 receptor family (IL17RAIL17RE) have been identified. The various receptor complexes through which each ligand is thought to induce signalling are shown, although it should be emphasized that in no case has the stoichiometry been shown definitively. The receptor for IL17D is unknown, as is Nature Reviews | Immunology the ligand for IL17RD or an IL17RAIL17RD pairing if indeed it exists (see ref. 75). CBAD, C/EBP activation domain; FN, fibronectin IIIlike domain; SEFIR, SEF/IL17R; TILL, TIRlike loop.
NATuRE REVIEwS | Immunology 2009 Macmillan Publishers Limited. All rights reserved VOLuME 9 | AuGuST 2009 | 559

REVIEWS
a
IL-17A-specific antibody IL-17F-specific antibody

b
IL-17RAFc fusion protein Fc portion of IgG FN2 Extracellular region of FN1 IL-17RA Mice only Humans only IL-17RCFc fusion protein

IL-17A

IL-17RA-specific antibody IL-17F IL-17RC-specific antibody

Soluble IL-17RA PLAD peptides

Figure 2 | Il-17R-binding complexes and strategies for therapeutic blockade of Il-17 signalling. The interleukin17 receptor (IL17R) complex contains an undetermined number of IL17RA and IL17RC subunits, although studies so far indicate that it might be at least trimeric, which is the form shown here. Both IL17A and IL17F signal Nature Reviews | Immunology through these subunits, although IL17A has far higher affinity for IL17RA than for IL17RC, whereas IL17F has a 21 greater affinity for IL17RC than for IL17RA (in humans) . Therefore, in humans soluble IL17RAFc affects the response to IL17A only, whereas soluble IL17RAFc affects the response to both IL17A and IL17F in mice. Many cytokinetargeting strategies have been proposed to block signalling through IL17R92. a | Antibodies specific for individual ligands or the individual receptor subunits are the most straightforward approach. b | In addition, soluble IL17R subunits, such as fusions to IgG Fc, have been evaluated in preclinical models (reviewed in ref. 93). c | Finally, preventing receptor assembly by means of soluble peptides containing the preligand assembly domain (PLAD) of IL17RA is another possible avenue for drug development, analogous to approaches used with tumour necrosis factor receptor signalling47,50. FN, fibronectin IIIlike domain.

Fluorescence resonance energy transfer

A technique that is used to measure proteinprotein 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.

factor receptors (TNFRs) and erythropoietin recep tor (EPOR; reviewed in refs 38,44). Mechanistically, preassembly poises a receptor to respond rapidly and specifically to a ligand. In the case of IL17RA, studies using fluorescence resonance energy transfer (FRET) to analyse interactions between IL17RA subunits showed that IL17RA forms ligandindependent complexes4547. Moreover, IL17RA coimmunoprecipitated with IL17RC in overexpression studies in a liganddependent manner, although it is not known whether IL17RC is preassembled with IL17RA to any degree35. The precise stoichiometry of the IL17Abinding recep tor complex has not been determined, but native gel analyses of IL17RC indicate the existence of a trimeric complex containing two IL17RA subunits and one IL17RC subunit 48. For preassembled receptors such as EPOR, ligand binding induces large conformational changes in the relative positions of the receptor subunits. This reori ents receptorbound cytoplasmic signalling molecules such as JAKs, facilitating interactions with appropriate substrates49. This might also apply for IL17RA because FRET between IL17RA molecules decreases following an interaction with a ligand45,46. One possible scenario is that IL17RA dimers dissociate after ligand binding and are replaced by IL17RAIL17RC heterodimers. Alternatively, IL17RC might be recruited to the IL17RA dimer to create a trimer or larger multimer, together with cytoplasmic signalling molecules such as ACT1. A better understanding of this process will be provided by the elucidation of the IL17RA crystal structure.

In the TNFR system, preassembly of the receptor is dictated by an extracellular cysteinerich motif known as a preligand assembly domain (PLAD). Soluble PLAD peptides have been shown to prevent TNFR assembly and thus block signalling in CIA50. Although it is structurally distinct from TNFRs, IL17RA contains a fibronectin III like PLAD that dimerizes in a yeast twohybrid system and is required for coimmunoprecipitation of IL17RA dimers45. unlike the TNFR system, in which the PLAD and ligandbinding site of the receptor are physically distinct, the IL17RA second fibronectin IIIlike motif is also an essential component of the IL17Abinding domain45. Consequently, strategies to block IL17A or its receptor could include soluble PLAD peptides as well as antibodies or soluble receptors47 (fIG. 2). IL17RA signalling: the NFB pathway. As IL17RA is not homologous to any known receptors13, it was not pos sible to investigate signal transduction simply by com paring it with other cytokine receptor systems. however, studies defining IL17Ainduced genes showed that IL17A activates a highly proinflammatory programme of gene expression, which is typical of that induced by innate immune receptors such as IL1Rs and TLRs51,52. Similarly to these receptors, IL17A activates NFB, a hallmark transcription factor associated with the induc tion of inflammation13 (fIG. 3a). Correspondingly, DNA elements that bind NFB in the promoters of several IL17A target genes are required for IL17Ainduced gene expression (reviewed in ref. 38). Gel shift studies indicated that IL17A activates p50 and p65, which are
www.nature.com/reviews/immunol

560 | AuGuST 2009 | VOLuME 9 2009 Macmillan Publishers Limited. All rights reserved

REVIEWS
a
IL-17RA Cell membrane Cytoplasm ? p38 MAPK IL-17RC IL-17A

TRAF6 and TRAF3 ACT1 TAK1

SEFIR TILL CBAD

PI3K?

? ?
P

ERK

C/EBP LAP C/EBP

C/EBP LAP*
P

mRNA stabilization

? AAAAAAA

Canonical NF-B pathway IB C/EBP

C/EBP

GSK3

Target gene transcription Nucleus IB NF-B IL-17R IL-17RC IL-17RA IL-17A

C/EBP C/EBP TLR

TIR Receptor motifs SEFIR TILL ACT1 ACT1 MYD88 TRIF Proximal adaptors IRF3

NF-B Transcription factors NF-B MAPKs C/EBP C/EBP Chemokines Cytokines Anti-inflammatory genes

MAPKs C/EBP C/EBP

Main gene products

Interferons Chemokines Cytokines Anti-inflammatory genes Co-stimulators

Figure 3 | Il-17-induced signalling pathways. a | Schematic depicting interleukin17 receptor (IL17R) signalling. The IL17R complex is composed of IL17RA and IL17RC. Both subunits encode SEF/IL17R (SEFIR) domains59, but a sequence similar to the Toll/IL1R (TIR) BBloop is found only in IL17RA, termed a TIRlike loop (TILL)43. IL17RA engages the SEFIR domaincontaining adaptor ACT1 to mediate various downstream events62. Specifically, ACT1 is required for recruitment of TNFRassociated factor 6 (TRAF6) and possibly TRAF3, which are essential upstream activators of the canonical nuclear factorB (NFB) pathway. It is not clear whether TRAF6 is also required for the activation of the mitogenactivated protein kinase (MAPK) p38. Act1/ cells fail to upregulate the expression of the liverenriched activator protein (LAP) and LAP* splice variants of CCAAT/enhancer binding protein (C/EBP) or the expression of C/EBP, another event that might be downstream of NFB58,63. ACT1, but not TRAF6, is required for IL17Ainduced stabilization of several target mRNAs, particularly those encoding chemokines and cytokines66. Interestingly, extracellular signalregulated kinase (ERK) might also be controlled, at least indirectly, by Nature Reviews | Immunology ACT1independent pathways, as Act1/ cells show strong upregulation of ERK phosphorylation 24 hours after IL17A stimulation63. ERK mediates rapid phosphorylation of C/EBP on threonine 188 (ref. 61). A second functional domain on IL17RA is located in the carboxyterminal region and is not required for efficient activation of NFB and MAPK pathways. however, deletion of this domain results in impaired alternative translation of C/EBP from the LAP isoform to the LAP* isoform43, and hence was termed the C/EBPactivation domain (CBAD). The CBAD is also required for IL17Amediated inducible phosphorylation of C/EBP on threonine 179, which is mediated by glycogen synthase kinase 3 (GSK3)61. b | Comparison of IL17R and Tolllike receptor (TLR) signalling. IL17R and TLR (or IL1R, not shown) signalling pathways use different functional receptor motifs (SEFIR and TILL versus Toll/IL1R (TIR) domains) and proximal adaptors (ACT1 versus MYD88 (myeloid differentiation primaryresponse protein 88) and TRIF (TIRdomaincontaining adaptor protein inducing IFN)), but converge on common pathways (NFB, C/EBP and MAPKs). Therefore, these receptors activate similar, although not identical, panels of downstream genes. IB, inhibitor of NFB; IRF3, interferon regulatory factor 3; P13K, phosphoinositide 3kinase.

NATuRE REVIEwS | Immunology 2009 Macmillan Publishers Limited. All rights reserved

VOLuME 9 | AuGuST 2009 | 561

REVIEWS
components of the canonical NfB pathway53, but so far there is no evidence that the noncanonical NfB pathway is involved in IL17RA signalling (S.L.G., unpublished observations). however, NFBinducing kinase (NIK), which is a component of the noncanonical pathway, was reported to be activated in response to IL17A54. IL17A also induces the expression of inhibitor of NFB (IB)51,55, which is a positive regulator of transcription triggered by the TLR and IL1R signalling pathways55. It is therefore likely that IB is involved in IL17A mediated gene expression, although this has not been clearly defined. A wide diversity of inflammatory stimuli activate NFB, but they accomplish this through distinct proximal signalling pathways56. The proximal activa tors of NFB in the IL17RA signalling pathway were unknown for a considerable length of time. hints as to their identity came from observations that IL17RA signalling had parallels with the IL1R and TLR sig nalling cascades. For example, TNFRassociated fac tor 6 (TRAF6) is a key adaptor protein in the IL1R and TLR signalling cascades, and fibroblasts from Traf6/ mice are defective in IL17Amediated induc tion of NFB activation57. As IL17RA does not have an obvious TRAF6binding motif, it was suggested that a signalling intermediate might be required to bridge IL17RA and TRAF6. however, molecules involved in proximal IL1R and TLR signalling, such as MyD88 (myeloid differentiation primary response protein 88), TRIF (TIR domaincontaining adaptor inducing IFN), IRAK4 (IL1Rassociated kinase 4) and IRAK1, are dispensable for IL17Amediated signalling 43,58 (F. Shen, L. Li and S.L.G., unpublished observations). Consequently, early IL17RA signalling intermediates are distinct from classical activators of innate immune responses (fIG. 3b). A key insight into IL17R signalling emerged from a bioinformatics analysis that identified a conserved motif in the cytoplasmic domains of IL17R family members that was homologous to the Toll/IL1r (TIr) domain9, which provides essential and specific docking sites for intracel lular adaptors such as MyD88. This study named the conserved IL17R region a SEFIR domain (see above). SEFIR domains lack certain elements found in proto typical TIR domains, potentially explaining why they do not engage TIRcontaining adaptors. Specifically, SEFIR domains lack the TIR box 3 subdomain and the BBloop59, which are crucial specificity determinants directing TIRbased proteinprotein interactions60. however, a region at the carboxyterminal side of the SEFIR domain in IL17RA has marked sequence homol ogy to BBloops. Deletion of or point mutations in this region render IL17RA nonfunctional, so this motif is referred to as a TIRlike loop (TILL)43,61. It is probable that the TILL provides a unique interaction surface for an asyetunknown signalling molecule, potentially serving as the TIR box 3 equivalent. Surprisingly, although all IL17Rs have a SEFIR motif, the TILL domain seems to be unique to IL17RA, perhaps explain ing why IL17RA functions as a common subunit shared by several receptors in the family (fIG. 1). A SEFIR domain is also present in ACT1, a sig nalling adaptor that was previously linked to NFB activation through B cell activating factor (BAFF) and CD40 ligand59. Indeed, ACT1 deficiency in knock out mice or generated by RNA interferencemediated knockdown impairs IL17A and IL17Finduced acti vation of NFB25,62 (fIG. 3). Coimmunoprecipitation studies indicate that ACT1 is recruited to IL17RA within 5 minutes of IL17A stimulation63. Supporting these observations, deletion of the SEFIR domain in IL17RA impairs the activation of NFB by IL17A43,63. unlike IL17RA, ACT1 contains a TRAF6binding motif and, accordingly, can bind TRAF6, TRAF3 and TGFactivated kinase 1 (TAK1)63. however, ACT1 independent pathways are also induced by IL17RA, as shown by the fact that extracellular signalregulated kinase 1 (ERK1) and ERK2 are activated in Act1/ cells in response to IL17A, albeit with delayed kinetics63. The crucial role of ACT1 in IL17RA signalling has recently been verified in a second knockout mouse model 26 . Intriguingly, the respiratory pathogen Chlamydia pneumoniae encodes an ACT1binding pro tein that seems to inhibit IL17RA signalling, presum ably providing a survival advantage to this organism64. Collectively, these studies illustrate that the proximal events in IL17RAmediated activation of NFB dif fer from those of TLRs and IL1Rs owing to unique structural components of IL17RA (fIG. 3b). IL17RA signalling: AP1, MAPK and mRNA stability. Another typical event induced by proinflammatory mediators is the activation of the mitogenactivated pro tein kinase (MAPK) signalling pathway, which leads to the activation of AP1 (activator protein 1). IL17A induces the activation of various MAPKs, but ERK is generally the most strongly and rapidly phosphorylated. Although AP1 binding sites are enriched in IL17A target promot ers42, the AP1 site in the mouse Il6 promoter is dispensa ble for IL17Ainduced activation53. The most important role of the MAPK pathway in IL17Ainduced signalling is controlling the stability of mRNA transcripts. MAPKs stabilize mRNA through the inhibition of destabilizing proteins such as tristetraprolin. Tristetraprolin binds to Aurich elements (AREs) in mRNA transcripts and delivers them to the exosome complex, where they are degraded. Phosphorylation of tristetraprolin by MAPKs blocks its ability to recruit the degradative machinery, thereby increasing mRNA transcript halflife (reviewed in ref. 65). Many IL17A target genes are chemokines or cytokines, the transcripts of which are destabilized by AREs located in the 3 untranslated region65. Numerous studies show that activation of MAPKs by IL17A significantly increases the concentration of these transcripts38. ACT1 is required for IL17Amediated stabilization of Cxcl1 (CXCchemokine ligand 1) mRNA, but TRAF6 is surpris ingly dispensable66. unexpectedly, the ability of IL17A to stabilize TNFinduced Cxcl1 mRNA is not compromised in tristetraprolindeficient fibroblasts (T. hamilton, per sonal communication). In addition to tristetraprolin, other proteins are involved in mediating cytokine mRNA stability, such as the recently described ZC3h12A67.
www.nature.com/reviews/immunol 2009 Macmillan Publishers Limited. All rights reserved

Canonical NFB pathway

A typical pathway of nuclear factorB (NfB) activation that involves phosphorylation and degradation of the prototypical NfB inhibitor, inhibitor of NfB (IB).

Noncanonical NFB pathway

A pathway of nuclear factorB (NfB) activation that does not involve inhibitor of NfB (IB) degradation but relies on the processing of an NfB precursor protein, p100, leading to nuclear translocation of the p52reLB NfB heterodimer.

Toll/IL1 receptor (TIR) domain

An intracellular signalling domain that is found in interleukin1 (IL1) receptor, Tolllike receptors and several adaptor proteins, including MYD88 (myeloid differentiation primary response protein 88).

BBloop
A structured loop linking the second helix and the second sheet within Toll/IL1 receptor (TIr) domains. This loop is a specificity determinant for TIr domains, and certain mutations in the BBloop cause impairment of Tolllike receptor signalling.

Exosome complex
A multiprotein complex that degrades various forms of rNA. Certain mrNA transcripts (particularly those encoding cytokines and chemokines) are inherently unstable owing to the presence of AUrich elements (Ares) located in the 3 untranslated region. Proteins that bind to Ares target these transcripts to the exosome complex for degradation.

562 | AuGuST 2009 | VOLuME 9

REVIEWS
Thus, there is clearly much more to learn about the mech anisms by which IL17A regulates mRNA transcript stability, but this is likely to be an important means by which inflammation is controlled by this cytokine. IL17RA signalling: CCAAT/enhancerbinding protein. IL17A is consistently found to be a weak activator of NFB, which indicates that additional transcription fac tors are involved in the response to IL17A. A microarray screen for IL17Ainduced genes identified the CCAAT/ enhancerbinding protein (C/EBP) transcription factors C/EBP and C/EBP as being involved in this proc ess53. The promoters of genes upregulated by IL17A are enriched for C/EBPbinding elements42, and activation of the Il6 and lcn2 (lipocalin 2; also known as 24p3) pro moters following IL17A stimulation requires C/EBP and C/EBP53. So, C/EBP and C/EBP are targets of IL17Ainduced signalling and also important mediators of IL17Ainduced signalling pathways. In some respects, C/EBP and C/EBP seem to func tion redundantly, as reconstitution of cells deficient in both C/EBP and C/EBP with either transcription fac tor can restore IL17Adependent induction of IL6 and lipocalin 2 expression53. Nonetheless, there are essential differences in how C/EBP and C/EBP are regulated by IL17RA. ACT1 and the SEFIR and TILL domains of IL17RA are required for the induction of C/EBP expression, suggesting a role for NFB in this proc ess43,58. This observation is consistent with a study show ing that NFB can bind directly to the Cebpd promoter following lipopolysaccharide stimulation68. C/EBP expression is regulated by IL17A in a more complex manner. C/EBP exists in three isoforms that are generated by alternative translation69. The largest is a full length isoform known as liverenriched activa tor 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 (liverenriched inhibitory protein) is also generated by alternative translation and acts as a dominantnegative inhibitor of transcription. The mechanism underlying these alternative translation events is not understood. IL17A treatment of fibroblast cell lines results in a mild induction of LAP, a large increase in LAP* and no induc tion of LIP. Induction of LAP* depends on the SEFIR and TILL domains of IL17RA, suggesting that this process is downstream of ACT1. Generation of LAP* also requires a poorly characterized Cterminal domain in IL17RA known as a C/EBPactivation domain (CBAD)43, which is not found in any other IL17R family member 61. As with many signalling effectors, posttranslational modifications such as phosphorylation are important for the activity of C/EBP69,70. IL17A triggers dual, sequen tial phosphorylation of a regulatory site within C/EBP. Specifically, ERK phosphorylates threonine 188 within 15 minutes of IL17A stimulation, and glycogen synthase kinase 3 (GSK3) phosphorylates threonine 179 after 1 hour, an event that requires prior phosphorylation at threonine 188 (ref. 61). Interestingly, these phospho rylation events are mediated by distinct subdomains of IL17RA (fIG. 3a). Regulation of ERK and hence
NATuRE REVIEwS | Immunology 2009 Macmillan Publishers Limited. All rights reserved

phosphorylation at threonine 188 is mediated by the SEFIR and TILL domains of IL17RA43, whereas regula tion of GSK3 is mediated by the CBAD. In other sys tems, PI3K signalling is upstream of GSK3, but standard PI3K inhibitors have no effect on IL17Ainduced signal ling in this setting. unexpectedly, the effect of C/EBP phosphorylation is to downregulate its transcriptional capacity, so this pathway is one of the few known inhibi tory signalling events mediated by IL17A61. Because induction, alternative translation and phosphorylation of C/EBP all occur during a time frame in which expres sion of C/EBP is also upregulated by IL17A through the canonical NFB pathway 51, there is a dynamic and complex interplay between members of the C/EBP family that could allow the detailed transcriptional control of C/EBPdependent 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 IL17R signalling 69. More broadly, these molecular events help to explain the synergism between IL17A and other cytokines, in particular TNF71. The mechanism underlying such syn ergy occurs partly through enhanced effects on mRNA stability 38,72, but C/EBP transcription factors also help to mediate cooperative activation of target promoters. For example, TNF and IL17A have an additive effect on the activation of the Il6 promoter, and overexpression of either C/EBP or C/EBP can replace the contribution of IL17A to this cooperative signal53. Other pathways activated by IL17RA. Additional events have been implicated in IL17RA signalling, although generally there is less evidence for these other pathways. Pharmacological inhibitors of JAKs have been reported to limit IL17Amediated signalling 73,74, but these results should be interpreted with caution owing to the nonspecific effects of such compounds. weak acti vation of STATs has also been reported, but secondary effects from IL17Ainduced secretion of cytokines such as IL6 were not ruled out satisfactorily 38. Activation of PI3K has also been observed; IL17Ainduced signalling in lung epithelial cells is associated with increased lipid phosphorylation, weak AKT phosphorylation and inhi bition by specific PI3K inhibitors73. however, there are few biochemical data indicating which PI3K isoforms are involved in this process. In addition, IL17RA, and hence downstream signalling from this receptor, might be controlled by inducible degradation. An overexpres sion study showed that IL17A triggers the ubiquityla tion and degradation of IL17RA, which might involve the E3 ubiquitin ligase TRAF6 (ref. 75).

Other receptors of the IL17R family IL17RC. IL17RC was identified by homology searches of mammalian expressed sequence tag (EST) data bases. Complementation studies showed that IL17RC is required for IL17A and IL17Fmediated signal ling, although it cannot induce signalling in the absence of IL17RA. This study also revealed an unexpected speciesdependent interaction between IL17R subunits. Specifically, mouse and human IL17A show no species
VOLuME 9 | AuGuST 2009 | 563

REVIEWS
dependence in signalling 13, whereas only mouse IL17RA can reconstitute IL17Adependent signalling in mouse Il17ra/ fibroblasts. Furthermore, coexpression of human but not mouse IL17RC with human IL17RA can restore signalling in these cells35. Consistently, fibroblasts from Il17rc/ mice fail to induce the production of IL6 or gran ulocyte/macrophage CSF (GMCSF) in response to either IL17A or IL17F76. The reason for this species depend ence is not clear, but it could be important in evaluating cytokinespecific therapeutics in preclinical models. The findings discussed above indicate that the IL17A binding complex is an obligate multimeric receptor containing both IL17RA and IL17RC. however, these subunits have reciprocal expression patterns, which is suggestive of tissuedependent activities21,22. In contrast to IL17RA, IL17RC expression is low in haematopoietic tissues and high in nonimmune cells of the prostate, liver, kidney, thyroid and joints21,77. In terms of biological signalling, it is conceivable that the differential expres sion of IL17R subunits could provide a mechanism for tissuespecific signalling by IL17A and/or IL17F. In humans IL17RA binds with an extremely low affinity to IL17F, whereas IL17RC binds with higher affinity to IL17F than to IL17A21, so cells with high IL17RC expression could be highly responsive to IL17F, whereas those with low IL17RC expression and high IL17RA expression might respond better to IL17A. The situation is somewhat different in mice, in which IL17RA binds both IL17A and IL17F, whereas IL17RC binds strongly only to IL17F. Studies in Il17a/ and Il17f / mice indi cated that IL17A but not IL17F mediates signals in mouse T cells, correlating with undetectable levels of IL17RC in these cells22. This raises the intriguing ques tion of whether IL17RA signals as a homomultimer in T cells or whether there is another subunit that might pair with IL17RA in certain cell types such as T cells. This information could also be used for therapeutic purposes; soluble IL17RA can efficiently block IL17Adependent but not IL17Fdependent responses in human cells, providing an avenue to selectively target individual cytokines21 (fIG. 2). Defining the precise nature of IL17 family cytokinebinding complexes in different tissues and also in mice and humans is therefore important for understanding signalling and devising ways in which to optimally target this system for clinical benefit. with the exception of IL17RA, other members of the IL17R family are highly spliced at sites in the extra cellular domain, potentially giving rise to both agonis tic and antagonistic (soluble) forms of the receptors. Indeed, more than 90 splice isoforms of IL17RC were identified in human prostate cancer lines 78, but only 4 splice variants of mouse IL17RC are found in EST databases21. Interestingly, there is ligand preference of IL17RC splice isoforms, as certain forms bind prefer entially to IL17A or IL17F. 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 might be important for directing the ability of a particular cell or tissue to respond to different IL17 family cytokines.
564 | AuGuST 2009 | VOLuME 9 2009 Macmillan Publishers Limited. All rights reserved

As expected, the IL17RC cytoplasmic tail is required for signal transduction35 but not for inducible coimmunoprecipitation with IL17RA (w. Ouyang, personal communication). So far, little is known about exactly how IL17RC participates in signalling. IL17RC contains a SEFIR domain but not an obvious TILL domain, and it is not known whether IL17RC binds directly to ACT1, TRAF6 or other downstream signalling molecules. It is tempting to speculate that IL17RC might recruit unique molecules to the receptor complex, but it is possible that IL17RC simply increases the number of ACT1 molecules in the complex to facilitate more efficient signal transduction. IL17RB. IL17RB binds both IL17B and IL17E. This subunit is expressed by various endocrine tissues as well as the kidneys, liver and Th2 cells79. Similarly to IL17RC, IL17RB is highly spliced in the extracellular domain80, although no evaluation of the role of each splice variant has been reported. Recent evidence indicates that IL17RB pairs with IL17RA to form a functional receptor complex for IL17E, but the specific contri bution 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 IL17A and IL17F could involve additional contri butions from IL17E. unlike IL17RA, IL17RB has a TRAF6binding motif in its cytoplasmic tail. As a result, antibodymediated crosslinking of the receptor activates NFB, which can be blocked by a dominantnegative form of TRAF6 but not TRAF2 (ref. 81). IL17E has been shown to activate NFATc1 (nuclear factor of activated T cells, cytoplasmic 1) and JuNB, leading to increased IL4 expression by Th2 cells82. Similar to the rest of the IL17R family, the IL17RB cytoplasmic tail contains a SEFIR domain and was recently shown to bind ACT1 in a SEFIRdependent manner. Accordingly, Act1/ mice show defects in responding to IL17E in vivo26,83. IL17RD. IL17RD has no known ligand (fIG. 1) . It was first identified in zebrafish on the basis of a simi lar expression pattern to the fibroblast growth factor receptor (FGFR) and thus is commonly known as SEF (similar expression to the FGFR). IL17RD seems to be the most evolutionarily ancient member of the IL17R family, as it has homologues in sea lamprey, frogs and C. elegans 84. Its role in zebrafish suggests that the original function of the IL17R family might have been to control development. Interestingly, this represents another parallel to the TLR family, as Toll from Drosophila melanogaster functions to control dorsoventral polarity during embryonic development. IL17RD inhibits FGFmediated RasMAPK and PI3K signalling during both zebrafish and frog devel opment 85. IL17RD blocks FGF in part by physically associating with FGFR1 and FGFR2. The cytoplasmic tail of IL17RD is required for its ability to inhibit sig nalling and associate with FGFR, but the extracellular domain is dispensable 85. The human homologue of IL17RD also coimmunoprecipitates with FGFR1 and can inhibit FGFdependent ERK activation and
www.nature.com/reviews/immunol

REVIEWS
Box 2 | Future avenues of investigation in the IL17R signalling field
There remain many unanswered questions with regard to interleukin-17 receptor (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 (or ligands) for IL-17RD (see also fIG. 1). The stoichiometry of the various receptor complexes is not well delineated, and there is no 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 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-17AIL-17F, the molecular contribution of the IL-17RC cytoplasmic tail is unknown, and a similar question exists for the IL-17RE subunit when paired with IL-17RA. The details of the nuclear factor-B (NF-B) pathway are not fully elucidated; for example, a possible role for inhibitor of NF-B- (I) is intriguing but undetermined. It is not known whether ACT1 (also known as CIKS) binds to additional signalling molecules or kinases that might have similar roles to IL-1R-associated kinases in the Toll-like receptor system. The signalling pathways leading to CCAAT/enhancer-binding protein (C/EBP) activation are incompletely elucidated. How does IL-17 control mRNA transcript stability? The role of IL-17 signalling in B and T cells is also not well understood. What is the contribution of IL-17R signalling pathways in vivo? What is the importance of a virally encoded IL-17A homologue in Herpesvirus saimiri? Future investigations will address these and other important questions.

FGFdependent proliferation8688. Although the mecha nism by which IL17RDmediated inhibition occurs is not defined, mouse IL17RD has been shown to inter act with TAK1 to activate the MAP2K4Jun Nterminal kinase signalling pathway 89. In addition to associating with FGFR, human IL17RD has been shown to form homodimers, although it is not clear whether these are functional86. IL17RD can also interact with IL17RA, although the biological importance of this association remains unclear 36. IL17RDdeficient mice are viable and have no obvious developmental abnormalities, but detailed phenotypic analysis has not yet been carried out (J. Tocker, personal communication). IL17RE. IL17RE is the least well understood member of the IL17R family, but recent studies suggest that its ligand is IL17C (S. Levin, personal communication). IL17RE is highly spliced, with six isoforms identified in EST databases. Ectopic expression of an EPORIL17RE construct in the myeloid BaF3 cell line indicated that this receptor might promote proliferation, but this occurred in a ligandindependent manner, which raises concerns about the validity of the assay system90.

Perspectives and implications The past decade has seen great success in exploiting cytokines for therapeutic intervention. For example, anti bodies and soluble receptors that neutralize TNF have revolutionized the treatment of autoimmune diseases91. Therapies that target IL1, IL6, IL12 and IL23, which affect the development and function of Th17 cells (as well as other Th17like cells that produce IL17A and related ligands), have also had success in the clinical setting or in
1. Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 23482357 (1986). Gor, D. O., Rose, N. R. & Greenspan, N. S. TH1TH2: a procrustean paradigm. Nature Immunol. 4, 503505 (2003). Steinman, L. A brief history of TH17, the first major revision in the T H1/T H2 hypothesis of T cellmediated tissue damage. Nature Med. 13, 139145 (2007). This review article outlines the history of discrepancies in the TH1TH2 cell paradigm, presented as a cautionary tale of the process of scientific inquiry. 4.

experimental trials. The roles of IL17 family cytokines in autoimmunity make this system an obvious target for clinical intervention92. Strategies include administer ing neutralizing antibodies specific for IL17A, IL17F or IL17AIL17F, or for IL17RA or IL17RC. Soluble receptors or PLAD peptides could also be used to block ligandreceptor interactions21,50 (fIG. 2). understanding which receptor subunit (or subunits) to target while avoiding deleterious effects on the host immune system will be integral for developing effective treatments. In this regard, the different affinity of each IL17R subunit for its ligand could be exploited to allow more selec tive inhibition; for example, in human cells soluble IL17RA reagents selectively block IL17A and prob ably the IL17AIL17F heterodimer, whereas soluble IL17RC blocks IL17A, IL17F and the IL17AIL17F heterodimer21. In exciting new developments, IL17A specific antibodies have shown promise in early trials for the treatment of psoriasis (D. Patel, personal com munication). Although current strategies target ligands or extracellular features of cytokine receptors, defining the downstream signal transduction mechanisms might also allow the development of small molecule inhibitors that block specific intracellular pathways. In summary, IL17A came to prominence as the signature cytokine of the new Th17 cell subset, and its unusual structure, receptor and proximal signalling path ways have presented new paradigms in cytokine biology. however, there are still many open questions pertaining to ligandreceptor relationships, molecular signalling events and functions of the IL17 family in vivo (BOX 2). The next few years will certainly see important new insights about this fascinating family of cytokines.
inflammation of the brain. Nature 421, 744748 (2003). 8. Ghilardi, N. & Ouyang, W. Targeting the development and effector functions of Th17 cells. Semin. Immunol. 19, 383393 (2007). 9. OQuinn, D., Palmer, M., Lee, Y. & Weaver, C. Emergence of the Th17 pathway and its role in host defense. Adv. Immunol. 99, 115163 (2008). 10. McGeachy, M. J. & Cua, D. J. Th17 cell differentiation: the long and winding road. Immunity 28, 445453 (2008). 11. Yu, J. & Gaffen, S. L. Interleukin17: a novel inflammatory cytokine that bridges innate and adaptive immunity. Front. Biosci. 13, 170177 (2008).

5.

2. 3.

6.

7.

Oppmann, B. et al. Novel p19 protein engages IL12p40 to form a cytokine, IL23, with biological activities similar as well as distinct from IL12. Immunity 13, 715725 (2000). Aggarwal, S., Ghilardi, N., Xie, M. H., De Sauvage, F. J. & Gurney, A. L. Interleukin 23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin 17. J. Biol. Chem. 3, 19101914 (2002). InfanteDuarte, C., Horton, H. F., Byrne, M. C. & Kamradt, T. Microbial lipopeptides induce the production of IL17 in Th cells. J. Immunol. 165, 61076115 (2000). Cua, D. J. et al. Interleukin23 rather than interleukin12 is the critical cytokine for autoimmune

NATuRE REVIEwS | Immunology 2009 Macmillan Publishers Limited. All rights reserved

VOLuME 9 | AuGuST 2009 | 565

REVIEWS
12. Rouvier, E., Luciani, M.F., Mattei, M.G., Denizot, F. & Golstein, P. CTLA8, cloned from an activated T cell, bearing AUrich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J. Immunol. 150, 54455456 (1993). 13. Yao, Z. et al. Herpesvirus Saimiri encodes a new cytokine, IL17, which binds to a novel cytokine receptor. Immunity 3, 811821 (1995). This report describes the cloning of the first IL17R family member, and is the first to show a role for NFB in IL17induced signal transduction. 14. Fossiez, F. et al. T cell interleukin17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 25932603 (1996). 15. Hymowitz, S. G. et al. IL17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL17F, and implications for receptor binding. EMBo J. 20, 53325341 (2001). 16. Tsutsui, S., Nakamura, O. & Watanabe, T. Lamprey (Lethenteron japonicum) IL17 upregulated by LPS stimulation in the skin cells. Immunogenetics 59, 873882 (2007). 17. Wright, J. F. et al. Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J. Biol. Chem. 282, 1344713455 (2007). 18. Chang, S. H. & Dong, C. A novel heterodimeric cytokine consisting of IL17 and IL17F regulates inflammatory responses. Cell Res. 17, 435440 (2007). 19. Yang, X. O. et al. Regulation of inflammatory responses by IL17F. J. Exp. Med. 205, 10631075 (2008). 20. Wright, J. F. et al. The human IL17F/IL17A heterodimeric cytokine signals through the IL17RA/ IL17RC receptor complex. J. Immunol. 181, 27992805 (2008). 21. Kuestner, R. et al. Identification of the IL17 receptor related molecule, IL17RC, as the receptor for IL17F. J. Immunol. 179, 54625473 (2007). This report shows that IL17RC binds with high affinity to IL17F. This is also the first functional analysis of different splice forms of any IL17R family member. 22. Ishigame, H. et al. Differential roles of interleukin17A and 17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108119 (2009). This report is the first to directly compare Il17a/ and Il17f/ mice and to show that these cytokines have markedly different functions in vivo. 23. Gaffen, S. L., Kramer, J. M., Yu, J. J. & Shen, F. in Vitamins and Hormones Vol. 74. (ed. G. Litwack) 255282 (Academic, London, 2006). 24. McAllister, F. et al. Role of IL17A, IL17F, and the IL17 receptor in regulating growthrelated oncogene and granulocyte colonystimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J. Immunol. 175, 404412 (2005). 25. Dong, C. Regulation and proinflammatory function of interleukin17 family cytokines. Immunol. Rev. 226, 8086 (2008). 26. Claudio, E. et al. The adaptor protein CIKS/Act1 is essential for IL25mediated allergic airway inflammation. J. Immunol. 182, 16171630 (2009). 27. Rickel, E. A. et al. Identification of functional roles for both IL17RB and IL17RA in mediating IL25induced activities. J. Immunol. 181, 42994310 (2008). This is the first report indicating that IL17RA functions as a shared receptor signalling subunit for IL17E and is required for its function in vivo. 28. Shi, Y. et al. A novel cytokine receptorligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity. J. Biol. Chem. 275, 1916719176 (2000). 29. Yamaguchi, Y. et al. IL17B and IL17C are associated with TNF production and contribute to the exacerbation of inflammatory arthritis. J. Immunol. 179, 71287136 (2007). 30. Hurst, S. D. et al. New IL17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL25. J. Immunol. 169, 443453 (2002). 31. Li, H. et al. Cloning and characterization of IL17B and IL17C, two new members of the IL17 family. Proc. Natl Acad. Sci. USA 97, 773778 (2000). 32. Starnes, T. et al. Cutting edge: IL17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J. Immunol. 167, 41374140 (2001). 33. Aggarwal, S. & Gurney, A. L. IL17: a prototype member of an emerging family. J. Leukoc. Biol. 71, 18 (2002). 34. Yao, Z. et al. Cutting edge: human IL17: a novel cytokine derived from T cells. J. Immunol. 155, 54835486 (1995). 35. Toy, D. et al. Cutting edge: interleukin17 signals through a heteromeric receptor complex. J. Immunol. 177, 3639 (2006). This report is the first to show that IL17RC is required for IL17Amediated signalling. 36. Rong, Z. et al. IL17RD (Sef or IL17RLM) interacts with IL17 receptor and mediates IL17 signaling. Cell Res. 19, 208215 (2008). 37. Ozaki, K. & Leonard, W. J. Cytokine and cytokine receptor pleiotropy and redundancy. J. Biol. Chem. 277, 2935529358 (2002). 38. Shen, F. & Gaffen, S. L. Structurefunction relationships in the IL17 receptor: implications for signal transduction and therapy. Cytokine 41, 92104 (2008). 39. Hsu, H. C. et al. Interleukin 17producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nature Immunol. 9, 166175 (2008). 40. Zeng, R. et al. Synergy of IL21 and IL15 in regulating CD8+ T cell expansion and function. J. Exp. Med. 201, 139148 (2005). 41. Lindemann, M. J., Hu, Z., Benczik, M., Liu, K. D. & Gaffen, S. L. Differential regulation of the IL17 receptor by c cytokines: inhibitory signaling by the phosphatidylinositol 3kinase pathway. J. Biol. Chem. 283, 1410014108 (2008). 42. Shen, F., Hu, Z., Goswami, J. & Gaffen, S. L. Identification of common transcriptional regulatory elements in interleukin17 target genes. J. Biol. Chem. 281, 2413824148 (2006). 43. Maitra, A. et al. Distinct functional motifs within the IL17 receptor regulate signal transduction and target gene expression. Proc. Natl Acad. Sci USA 104, 75067511 (2007). This is the first detailed mutagenesis study of IL17RA; it reveals a functional role for the SEFIR domain and includes the first description of the TILL domain and CBAD, which seem to be unique to IL17RA. 44. Chan, F. K. Three is better than one: preligand receptor assembly in the regulation of TNF receptor signaling. Cytokine 37, 101107 (2007). 45. Kramer, J. et al. Cutting edge: identification of the preligand assembly domain (PLAD) and ligand binding site in the IL17 receptor. J. Immunol. 179, 63796383 (2007). 46. Kramer, J. et al. Cutting edge: evidence for ligand independent multimerization of the IL17 receptor. J. Immunol. 176, 711715 (2006). 47. Kramer, J. & Gaffen, S. Interleukin17: a new paradigm in inflammation, autoimmunity and therapy. J. Periodontol. 78, 10831093 (2007). 48. You, Z. et al. Interleukin17 receptorlike gene is a novel antiapoptotic gene highly expressed in androgenindependent prostate cancer. Cancer Res. 66, 175183 (2006). 49. Remy, I., Wilson, I. A. & Michnick, S. W. Erythropietin receptor activation by a ligandinduced conformation change. Science 283, 990993 (1999). 50. Deng, G. M., Zheng, L., Chan, F. K. & Lenardo, M. Amelioration of inflammatory arthritis by targeting the preligand assembly domain of tumor necrosis factor receptors. Nature Med. 11, 10661072 (2005). 51. Shen, F., Ruddy, M. J., Plamondon, P. & Gaffen, S. L. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin17 and TNFinduced genes in bone cells. J. Leukoc. Biol. 77, 388399 (2005). 52. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 11331141 (2005). 53. Ruddy, M. J. et al. Functional cooperation between interleukin17 and tumor necrosis factor is mediated by CCAAT/enhancer binding protein family members. J. Biol. Chem. 279, 25592567 (2004). This is the first paper to show a role for C/EBP proteins in IL17induced signalling. 54. Awane, M., Andres, P. G., Li, D. J. & Reinecker, H. C. NFBinducing kinase is a common mediator of IL17, TNF, and IL1 induced chemokine promoter activation in intestinal epithelial cells. J. Immunol. 162, 53375344 (1999). 55. Yamazaki, S., Muta, T., Matsuo, S. & Takeshige, K. Stimulusspecific induction of a novel nuclear factorB regulator, IB, via Toll/Interleukin1 receptor is mediated by mRNA stabilization. J. Biol. Chem. 280, 16781687 (2005). 56. Blonska, M. & Lin, X. CARMA1mediated NFB and JNK activation in lymphocytes. Immunol. Rev. 228, 199211 (2009). 57. Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factorassociated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 12331239 (2000). 58. Chang, S. H., Park, H. & Dong, C. Act1 adaptor protein is an immediate and essential signaling component of interleukin17 receptor. J. Biol. Chem. 281, 3560335607 (2006). 59. Novatchkova, M., Leibbrandt, A., Werzowa, J., Neubuser, A. & Eisenhaber, F. The STIRdomain superfamily in signal transduction, development and immunity. Trends Biochem. Sci. 28, 226229 (2003). This is a groundbreaking bioinformatic analysis describing the SEFIR domain, a motif that is found in members of the IL17R family and in ACT1 and that is homologous to TIR domains. 60. Toshchakov, V. & Vogel, S. Cellpenetrating TIR BB loop decoy peptides: A novel class of TLR signaling inhibitors and a tool to study topology of TIRTIR interactions. Expt. op. Biol. Ther. 7, 10351050 (2007). 61. Shen, F. et al. IL17 receptor signaling inhibits C/EBP by sequential phosphorylation of the regulatory 2 domain. Sci. Signal. 2, ra8 (2009). 62. Linden, A. A role for the cytoplasmic adaptor proteins Act1 in mediating IL17 signaling. Sci. STKE 2007, re4 (2007). 63. Qian, Y. et al. The adaptor Act1 is required for interleukin 17dependent signaling associated with autoimmune and inflammatory disease. Nature Immunol. 8, 247256 (2007). This study, together with reference 58, is the first to show that ACT1 binds to IL17RA and is required for downstream signalling. 64. Wolf, K., Plano, G. V. & Fields, K. A. A protein secreted by the respiratory pathogen Chlamydia pneumoniae impairs IL17 signaling via interaction with human Act1. Cell. Microbiol. 11, 769779 (2009). 65. Anderson, P. Posttranscriptional control of cytokine production. Nature Immunol. 9, 353359 (2008). 66. Hartupee, J. et al. IL17 signaling for mRNA stabilization does not require TNF receptorassociated factor 6. J. Immunol. 182, 16601666 (2009). 67. Matsushita, K. et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 11851190 (2009). 68. Litvak, V. et al. Function of C/EBP in a regulatory circuit that discriminates between transient and persistent TLR4induced signals. Nature Immunol. 10, 437443 (2009). 69. Ramji, D. P. & Foka, P. CCAAT/enhancerbinding proteins: structure, function and regulation. Biochem. J. 365, 561575 (2002). 70. Tang, Q. Q. et al. Sequential phosphorylation of CCAAT enhancerbinding protein by MAPK and glycogen synthase kinase 3 is required for adipogenesis. Proc. Natl Acad. Sci. USA 102, 97669771 (2005). 71. Miossec, P. Interleukin17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum. 48, 594601 (2003). 72. Hartupee, J., Liu, C., Novotny, M., Li, X. & Hamilton, T. IL17 enhances chemokine gene expression through mRNA stabilization. J. Immunol. 179, 41354141 (2007). 73. Huang, F. et al. Requirement for both JAKmediated PI3K signaling and ACT1/TRAF6/TAK1dependent NFB activation by IL17A in enhancing cytokine expression in human airway epithelial cells. J. Immunol. 179, 65046513 (2007). 74. Kim, K. W. et al. Increased interleukin17 production via a phosphoinositide 3kinase/Akt and nuclear factor Bdependent pathway in patients with rheumatoid arthritis. Arthritis Res. Ther. 7, R139R148 (2005). 75. Rong, Z. et al. Interleukin17F signaling requires ubiquitination of interleukin17 receptor via TRAF6. Cell Signal. 19, 15141520 (2007). 76. Zheng, Y. et al. Interleukin22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282289 (2008).

566 | AuGuST 2009 | VOLuME 9 2009 Macmillan Publishers Limited. All rights reserved

www.nature.com/reviews/immunol

REVIEWS
77. Haudenschild, D., Moseley, T., Rose, L. & Reddi, A. H. Soluble and transmembrane isoforms of novel interleukin17 receptorlike protein by RNA splicing and expression in prostate cancer. J. Biol. Chem. 277, 43094316 (2002). 78. Haudenschild, D. R., Curtiss, S. B., Moseley, T. A. & Reddi, A. H. Generation of interleukin17 receptorlike protein (IL17RL) in prostate by alternative splicing of RNA. Prostate 66, 12681274 (2006). 79. Lee, J. et al. IL17E, a novel proinflammatory ligand for the IL17 receptor homolog IL17Rh1. J. Biol. Chem. 276, 16601664 (2001). 80. Moseley, T. A., Haudenschild, D. R., Rose, L. & Reddi, A. H. Interleukin17 family and IL17 receptors. Cytokine Growth Factor Rev. 14, 155174 (2003). 81. Maezawa, Y. et al. Involvement of TNF receptor associated factor 6 in IL25 receptor signaling. J. Immunol. 176, 10131018 (2006). 82. Angkasekwinai, P. et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 15091517 (2007). 83. Swaidani, S. et al. The critical role of epithelial derived Act1 in IL17 and IL25mediated pulmonary inflammation. J. Immunol. 182, 16311640 (2009). 84. Pancer, Z., Mayer, W. E., Klein, J. & Cooper, M. D. Prototypic T cell receptor and CD4like coreceptor are expressed by lymphocytes in the agnathan sea lamprey. Proc. Natl Acad. Sci USA 101, 1327313278 (2004). 85. Tsang, M., Friesel, R., Kudoh, T. & Dawid, I. Identification of Sef, a novel modulator of FGF signalling. Nature Cell Biol. 4, 165169 (2002). 86. Yang, R. B. et al. A novel interleukin17 receptorlike protein identified in human umbilical vein endothelial cells antagonizes basic fibroblast growth factor induced signaling. J. Biol. Chem. 278, 3323233238 (2003). 87. Xiong, S. et al. hSef inhibits PC12 cell differentiation by interfering with Rasmitogenactivated protein kinase MAPK signaling. J. Biol. Chem. 278, 5027350282 (2003). 88. Preger, E. et al. Alternative splicing generates an isoform of the human Sef gene with altered subcellular localization and specificity. Proc. Natl Acad. Sci. USA 101, 12291234 (2004). 89. Yang, X. et al. Sef interacts with TAK1 and mediates JNK activation and apoptosis. J. Biol. Chem. 279, 3809938102 (2004). 90. Li, T. S., Li, X. N., Chang, Z. J., Fu, X. Y. & Liu, L. Identification and functional characterization of a novel interleukin 17 receptor: a possible mitogenic activation through ras/mitogenactivated protein kinase signaling pathway. Cell Signal. 18, 12871298 (2006). McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nature Rev. Immunol. 7, 429442 (2007). Kikly, K., Liu, L., Na, S. & Sedgwick, J. D. The IL23/ Th17 axis: therapeutic targets for autoimmune inflammation. Curr. opin. Immunol. 18, 670675 (2006). Lubberts, E. IL17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 41, 8491 (2008). Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colonystimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med 194, 519527 (2001). Chabaud, M., Lubberts, E., Joosten, L., van Den Berg, W. & Miossec, P. IL17 derived from juxtaarticular bone and synovium contributes to joint degradation in rheumatoid arthritis. Arthritis Res. 3, 168177 (2001). Lubberts, E. et al. IL1independent role of IL17 in synovial inflammation and joint destruction during collageninduced arthritis. J. Immunol. 167, 10041013 (2001). Murphy, C. A. et al. Divergent pro and antiinflammatory roles for IL23 and IL12 in joint autoimmune inflammation. J. Exp. Med 198, 19511957 (2003). Harrington, L. E. et al. Interleukin 17producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunol. 6, 11231132 (2005). Langrish, C. L. et al. IL23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med 201, 233240 (2005). Duerr, R. H. et al. A Genomewide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 14611463 (2006). Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGF in the context of an inflammatory cytokine milieu supports de novo differentiation of IL17producing T cells. Immunity 24, 179189 (2006). Mangan, P. R. et al. Transforming growth factor induces development of the T H17 lineage. Nature 441, 231234 (2006). Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector T H17 and regulatory T cells. Nature 441, 235238 (2006). 104. Ivanov, I. et al. The orphan nuclear receptor RORT directs the differentiation program of proinflammatory IL17+ T helper cells. Cell 126, 11211133 (2006). 105. Liang, S. C. et al. Interleukin (IL)22 and IL17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med 203, 22712279 (2006). 106. Korn, T. et al. IL21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484487 (2007). 107. Nurieva, R. et al. Essential autocrine regulation by IL21 in the generation of inflammatory T cells. Nature 448, 480483 (2007). 108. Zhou, L. et al. IL6 programs T H17 cell differentiation by promoting sequential engagement of the IL21 and IL23 pathways. Nature Immunol. 8, 967974 (2007). 109. Milner, J. D. et al. Impaired T H17 cell differentiation in subjects with autosomal dominant hyperIgE syndrome. Nature 452, 773776 (2008).

91. 92.

93. 94.

95.

96.

Competing financial interests

The author declares competing financial interests: see web version for details.

97.

Acknowledgements

98.

99. 100. 101.

I thank J. Tocker (Amgen, Seattle, Washington, USA), S. Levin (Zymogenetics, Seattle, Washington, USA), W. Ouyang (Genentech, South San Francisco, California, USA), L. Li (Virginia Polytechnic University, Blacksburg, Virginia, USA), T. Hamilton (Cleveland Clinic, Cleveland, Ohio, USA) and D. Patel (Novartis, Basel, Switzerland) for sharing unpublished information. I thank D. Ascherman, R. Onishi, S. Khader, F. Shen and C. Dong for critical reading. S.L.G. was supported by grants from the National Institutes of Health, USA (AR054389, DE018822).

DATABASES
UniProtKB: http://www.uniprot.org ACT1 | C/EBP | C/EBP | IL17A | IL17B | IL17C | IL17D | IL17E | IL17F | IL17RA | IL17RB | IL17RC | IL17RD | IL17RE | p50 | p65 | TRAF6 | vIL17

102. 103.

FURTHER INFORMATION
Sarah L. Gaffens homepage: http://immunology.medicine.pitt.edu/personnelDetail.asp? pid=3714&id=37&ptype=&pnavcat=2
All lInks ARE ActIvE In thE onlInE pdF

NATuRE REVIEwS | Immunology 2009 Macmillan Publishers Limited. All rights reserved

VOLuME 9 | AuGuST 2009 | 567