Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Structure and signalling in the IL-17 receptor family

A Corrigendum to this article was published on 07 August 2009

Key Points

  • The cytokine IL-17A came into the limelight with the discovery of T helper 17 (TH17) cells, a new CD4+ T cell subset that represents the first main revision of the TH1–TH2 cell paradigm in 2 decades. IL-17A and its receptor are founding members of a new family of cytokines (IL-17A–IL-17F) and cytokine receptors (IL-17RA–IL-17RE) that have 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 family and seems to function as a co-receptor with at least two other members of the IL-17R 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 SEF/IL-17R (SEFIR) domain, which is conserved between but also unique to the IL-17R family, IL-17RA engages the ACT1 adaptor to induce the nuclear factor-κB, mitogen-activated protein kinase and CCAAT/enhancer-binding protein signalling pathways.

  • IL-17RC is a co-receptor with IL-17RA that triggers IL-17A- and IL-17F-mediated signalling, and IL-17RB associates with IL-17RA to mediate IL-17E-induced 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 cytokine family will provide useful information for therapeutic uses.

Abstract

Interleukin-17A (IL-17A), 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. IL-17A and its receptor (IL-17RA) 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 IL-17R 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 IL-17R family to mediate downstream events.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: IL-17R family ligand–receptor relationships and main structural features.
Figure 2: IL-17R-binding complexes and strategies for therapeutic blockade of IL-17 signalling.
Figure 3: IL-17-induced signalling pathways.

References

  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, 2348–2357 (1986).

    CAS  PubMed  Google Scholar 

  2. Gor, D. O., Rose, N. R. & Greenspan, N. S. TH1–TH2: a procrustean paradigm. Nature Immunol. 4, 503–505 (2003).

    CAS  Article  Google Scholar 

  3. Steinman, L. A brief history of TH17, the first major revision in the T H1/TH2 hypothesis of T cell-mediated tissue damage. Nature Med. 13, 139–145 (2007). This review article outlines the history of discrepancies in the T H 1–T H 2 cell paradigm, presented as a 'cautionary tale' of the process of scientific inquiry.

    CAS  PubMed  Article  Google Scholar 

  4. Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715–725 (2000).

    CAS  PubMed  Article  Google Scholar 

  5. 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, 1910–1914 (2002).

    Google Scholar 

  6. Infante-Duarte, C., Horton, H. F., Byrne, M. C. & Kamradt, T. Microbial lipopeptides induce the production of IL-17 in Th cells. J. Immunol. 165, 6107–6115 (2000).

    CAS  PubMed  Article  Google Scholar 

  7. Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    CAS  PubMed  Article  Google Scholar 

  8. Ghilardi, N. & Ouyang, W. Targeting the development and effector functions of Th17 cells. Semin. Immunol. 19, 383–393 (2007).

    CAS  PubMed  Article  Google Scholar 

  9. O'Quinn, D., Palmer, M., Lee, Y. & Weaver, C. Emergence of the Th17 pathway and its role in host defense. Adv. Immunol. 99, 115–163 (2008).

    CAS  PubMed  Article  Google Scholar 

  10. McGeachy, M. J. & Cua, D. J. Th17 cell differentiation: the long and winding road. Immunity 28, 445–453 (2008).

    CAS  PubMed  Article  Google Scholar 

  11. Yu, J. & Gaffen, S. L. Interleukin-17: a novel inflammatory cytokine that bridges innate and adaptive immunity. Front. Biosci. 13, 170–177 (2008).

    CAS  PubMed  Article  Google Scholar 

  12. Rouvier, E., Luciani, M.-F., Mattei, M.-G., Denizot, F. & Golstein, P. CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J. Immunol. 150, 5445–5456 (1993).

    CAS  PubMed  Google Scholar 

  13. Yao, Z. et al. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3, 811–821 (1995). This report describes the cloning of the first IL-17R family member, and is the first to show a role for NF-κB in IL-17-induced signal transduction.

    CAS  PubMed  Article  Google Scholar 

  14. Fossiez, F. et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J. Exp. Med. 183, 2593–2603 (1996).

    CAS  PubMed  Article  Google Scholar 

  15. Hymowitz, S. G. et al. IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. Embo J. 20, 5332–5341 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Tsutsui, S., Nakamura, O. & Watanabe, T. Lamprey (Lethenteron japonicum) IL-17 upregulated by LPS-stimulation in the skin cells. Immunogenetics 59, 873–882 (2007).

    CAS  PubMed  Article  Google Scholar 

  17. Wright, J. F. et al. Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J. Biol. Chem. 282, 13447–13455 (2007).

    CAS  PubMed  Article  Google Scholar 

  18. Chang, S. H. & Dong, C. A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res. 17, 435–440 (2007).

    PubMed  Article  CAS  Google Scholar 

  19. Yang, X. O. et al. Regulation of inflammatory responses by IL-17F. J. Exp. Med. 205, 1063–1075 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Wright, J. F. et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J. Immunol. 181, 2799–2805 (2008).

    CAS  PubMed  Article  Google Scholar 

  21. Kuestner, R. et al. Identification of the IL-17 receptor related molecule, IL-17RC, as the receptor for IL-17F. J. Immunol. 179, 5462–5473 (2007). This report shows that IL-17RC binds with high affinity to IL-17F. This is also the first functional analysis of different splice forms of any IL-17R family member.

    CAS  PubMed  Article  Google Scholar 

  22. Ishigame, H. et al. Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30, 108–119 (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.

    CAS  PubMed  Article  Google Scholar 

  23. Gaffen, S. L., Kramer, J. M., Yu, J. J. & Shen, F. in Vitamins and Hormones Vol. 74. (ed. G. Litwack) 255–282 (Academic, London, 2006).

    Google Scholar 

  24. McAllister, F. et al. Role of IL-17A, IL-17F, and the IL-17 receptor in regulating growth-related oncogene-α and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J. Immunol. 175, 404–412 (2005).

    CAS  PubMed  Article  Google Scholar 

  25. Dong, C. Regulation and pro-inflammatory function of interleukin-17 family cytokines. Immunol. Rev. 226, 80–86 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Claudio, E. et al. The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation. J. Immunol. 182, 1617–1630 (2009).

    CAS  PubMed  Article  Google Scholar 

  27. Rickel, E. A. et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J. Immunol. 181, 4299–4310 (2008). This is the first report indicating that IL-17RA functions as a shared receptor signalling subunit for IL-17E and is required for its function in vivo .

    CAS  PubMed  Article  Google Scholar 

  28. Shi, Y. et al. A novel cytokine receptor–ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity. J. Biol. Chem. 275, 19167–19176 (2000).

    CAS  PubMed  Article  Google Scholar 

  29. Yamaguchi, Y. et al. IL-17B and IL-17C are associated with TNF-α production and contribute to the exacerbation of inflammatory arthritis. J. Immunol. 179, 7128–7136 (2007).

    CAS  PubMed  Article  Google Scholar 

  30. Hurst, S. D. et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 169, 443–453 (2002).

    CAS  PubMed  Article  Google Scholar 

  31. Li, H. et al. Cloning and characterization of IL-17B and IL-17C, two new members of the IL-17 family. Proc. Natl Acad. Sci. USA 97, 773–778 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. Starnes, T. et al. Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J. Immunol. 167, 4137–4140 (2001).

    CAS  PubMed  Article  Google Scholar 

  33. Aggarwal, S. & Gurney, A. L. IL-17: a prototype member of an emerging family. J. Leukoc. Biol. 71, 1–8 (2002).

    CAS  PubMed  Google Scholar 

  34. Yao, Z. et al. Cutting edge: human IL-17: a novel cytokine derived from T cells. J. Immunol. 155, 5483–5486 (1995).

    CAS  PubMed  Google Scholar 

  35. Toy, D. et al. Cutting edge: interleukin-17 signals through a heteromeric receptor complex. J. Immunol. 177, 36–39 (2006). This report is the first to show that IL-17RC is required for IL-17A-mediated signalling.

    CAS  PubMed  Article  Google Scholar 

  36. Rong, Z. et al. IL-17RD (Sef or IL-17RLM) interacts with IL-17 receptor and mediates IL-17 signaling. Cell Res. 19, 208–215 (2008).

    Article  CAS  Google Scholar 

  37. Ozaki, K. & Leonard, W. J. Cytokine and cytokine receptor pleiotropy and redundancy. J. Biol. Chem. 277, 29355–29358 (2002).

    CAS  PubMed  Article  Google Scholar 

  38. Shen, F. & Gaffen, S. L. Structure–function relationships in the IL-17 receptor: implications for signal transduction and therapy. Cytokine 41, 92–104 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Hsu, H. C. et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nature Immunol. 9, 166–175 (2008).

    CAS  Article  Google Scholar 

  40. Zeng, R. et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med. 201, 139–148 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Lindemann, M. J., Hu, Z., Benczik, M., Liu, K. D. & Gaffen, S. L. Differential regulation of the IL-17 receptor by γ-c cytokines: inhibitory signaling by the phosphatidylinositol 3-kinase pathway. J. Biol. Chem. 283, 14100–14108 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Shen, F., Hu, Z., Goswami, J. & Gaffen, S. L. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J. Biol. Chem. 281, 24138–24148 (2006).

    CAS  PubMed  Article  Google Scholar 

  43. Maitra, A. et al. Distinct functional motifs within the IL-17 receptor regulate signal transduction and target gene expression. Proc. Natl Acad. Sci USA 104, 7506–7511 (2007). This is the first detailed mutagenesis study of IL-17RA; 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 IL-17RA.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. Chan, F. K. Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling. Cytokine 37, 101–107 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Kramer, J. et al. Cutting edge: identification of the pre-ligand assembly domain (PLAD) and ligand binding site in the IL-17 receptor. J. Immunol. 179, 6379–6383 (2007).

    CAS  PubMed  Article  Google Scholar 

  46. Kramer, J. et al. Cutting edge: evidence for ligand-independent multimerization of the IL-17 receptor. J. Immunol. 176, 711–715 (2006).

    CAS  PubMed  Article  Google Scholar 

  47. Kramer, J. & Gaffen, S. Interleukin-17: a new paradigm in inflammation, autoimmunity and therapy. J. Periodontol. 78, 1083–1093 (2007).

    PubMed  Article  Google Scholar 

  48. You, Z. et al. Interleukin-17 receptor-like gene is a novel antiapoptotic gene highly expressed in androgen-independent prostate cancer. Cancer Res. 66, 175–183 (2006).

    CAS  PubMed  Article  Google Scholar 

  49. Remy, I., Wilson, I. A. & Michnick, S. W. Erythropietin receptor activation by a ligand-induced conformation change. Science 283, 990–993 (1999).

    CAS  PubMed  Article  Google Scholar 

  50. Deng, G. M., Zheng, L., Chan, F. K. & Lenardo, M. Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors. Nature Med. 11, 1066–1072 (2005).

    CAS  PubMed  Article  Google Scholar 

  51. Shen, F., Ruddy, M. J., Plamondon, P. & Gaffen, S. L. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-α-induced genes in bone cells. J. Leukoc. Biol. 77, 388–399 (2005).

    CAS  PubMed  Article  Google Scholar 

  52. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nature Immunol. 6, 1133–1141 (2005).

    CAS  Article  Google Scholar 

  53. Ruddy, M. J. et al. Functional cooperation between interleukin-17 and tumor necrosis factor-α is mediated by CCAAT/enhancer binding protein family members. J. Biol. Chem. 279, 2559–2567 (2004). This is the first paper to show a role for C/EBP proteins in IL-17-induced signalling.

    CAS  PubMed  Article  Google Scholar 

  54. Awane, M., Andres, P. G., Li, D. J. & Reinecker, H. C. NF-κB-inducing kinase is a common mediator of IL-17-, TNF-α-, and IL-1 β-induced chemokine promoter activation in intestinal epithelial cells. J. Immunol. 162, 5337–5344 (1999).

    CAS  PubMed  Google Scholar 

  55. Yamazaki, S., Muta, T., Matsuo, S. & Takeshige, K. Stimulus-specific induction of a novel nuclear factor-κB regulator, IκB-ζ, via Toll/Interleukin-1 receptor is mediated by mRNA stabilization. J. Biol. Chem. 280, 1678–1687 (2005).

    CAS  PubMed  Article  Google Scholar 

  56. Blonska, M. & Lin, X. CARMA1-mediated NF-κB and JNK activation in lymphocytes. Immunol. Rev. 228, 199–211 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Schwandner, R., Yamaguchi, K. & Cao, Z. Requirement of tumor necrosis factor-associated factor (TRAF)6 in interleukin 17 signal transduction. J. Exp. Med. 191, 1233–1239 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Chang, S. H., Park, H. & Dong, C. Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor. J. Biol. Chem. 281, 35603–35607 (2006).

    CAS  PubMed  Article  Google Scholar 

  59. Novatchkova, M., Leibbrandt, A., Werzowa, J., Neubuser, A. & Eisenhaber, F. The STIR-domain superfamily in signal transduction, development and immunity. Trends Biochem. Sci. 28, 226–229 (2003). This is a groundbreaking bioinformatic analysis describing the SEFIR domain, a motif that is found in members of the IL-17R family and in ACT1 and that is homologous to TIR domains.

    CAS  PubMed  Article  Google Scholar 

  60. Toshchakov, V. & Vogel, S. Cell-penetrating TIR BB loop decoy peptides: A novel class of TLR signaling inhibitors and a tool to study topology of TIR–TIR interactions. Expt. Op. Biol. Ther. 7, 1035–1050 (2007).

    CAS  Article  Google Scholar 

  61. Shen, F. et al. IL-17 receptor signaling inhibits C/EBPβ by sequential phosphorylation of the regulatory 2 domain. Sci. Signal. 2, ra8 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  62. Linden, A. A role for the cytoplasmic adaptor proteins Act1 in mediating IL-17 signaling. Sci. STKE 2007, re4 (2007).

    PubMed  Article  Google Scholar 

  63. Qian, Y. et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nature Immunol. 8, 247–256 (2007). This study, together with reference 58, is the first to show that ACT1 binds to IL-17RA and is required for downstream signalling.

    CAS  Article  Google Scholar 

  64. Wolf, K., Plano, G. V. & Fields, K. A. A protein secreted by the respiratory pathogen Chlamydia pneumoniae impairs IL-17 signaling via interaction with human Act1. Cell. Microbiol. 11, 769–779 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Anderson, P. Post-transcriptional control of cytokine production. Nature Immunol. 9, 353–359 (2008).

    CAS  Article  Google Scholar 

  66. Hartupee, J. et al. IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6. J. Immunol. 182, 1660–1666 (2009).

    CAS  PubMed  Article  Google Scholar 

  67. Matsushita, K. et al. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature 458, 1185–1190 (2009).

    CAS  PubMed  Article  Google Scholar 

  68. Litvak, V. et al. Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals. Nature Immunol. 10, 437–443 (2009).

    CAS  Article  Google Scholar 

  69. Ramji, D. P. & Foka, P. CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem. J. 365, 561–575 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Tang, Q. Q. et al. Sequential phosphorylation of CCAAT enhancer-binding protein β by MAPK and glycogen synthase kinase 3β is required for adipogenesis. Proc. Natl Acad. Sci. USA 102, 9766–9771 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. Miossec, P. Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum. 48, 594–601 (2003).

    CAS  PubMed  Article  Google Scholar 

  72. Hartupee, J., Liu, C., Novotny, M., Li, X. & Hamilton, T. IL-17 enhances chemokine gene expression through mRNA stabilization. J. Immunol. 179, 4135–4141 (2007).

    CAS  PubMed  Article  Google Scholar 

  73. Huang, F. et al. Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-κB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells. J. Immunol. 179, 6504–6513 (2007).

    CAS  PubMed  Article  Google Scholar 

  74. Kim, K. W. et al. Increased interleukin-17 production via a phosphoinositide 3-kinase/Akt and nuclear factor κB-dependent pathway in patients with rheumatoid arthritis. Arthritis Res. Ther. 7, R139–R148 (2005).

    CAS  PubMed  Article  Google Scholar 

  75. Rong, Z. et al. Interleukin-17F signaling requires ubiquitination of interleukin-17 receptor via TRAF6. Cell Signal. 19, 1514–1520 (2007).

    CAS  PubMed  Article  Google Scholar 

  76. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008).

    CAS  PubMed  Article  Google Scholar 

  77. Haudenschild, D., Moseley, T., Rose, L. & Reddi, A. H. Soluble and transmembrane isoforms of novel interleukin-17 receptor-like protein by RNA splicing and expression in prostate cancer. J. Biol. Chem. 277, 4309–4316 (2002).

    CAS  PubMed  Article  Google Scholar 

  78. Haudenschild, D. R., Curtiss, S. B., Moseley, T. A. & Reddi, A. H. Generation of interleukin-17 receptor-like protein (IL-17RL) in prostate by alternative splicing of RNA. Prostate 66, 1268–1274 (2006).

    CAS  PubMed  Article  Google Scholar 

  79. Lee, J. et al. IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J. Biol. Chem. 276, 1660–1664 (2001).

    CAS  PubMed  Article  Google Scholar 

  80. Moseley, T. A., Haudenschild, D. R., Rose, L. & Reddi, A. H. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 14, 155–174 (2003).

    CAS  PubMed  Article  Google Scholar 

  81. Maezawa, Y. et al. Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling. J. Immunol. 176, 1013–1018 (2006).

    CAS  PubMed  Article  Google Scholar 

  82. Angkasekwinai, P. et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 1509–1517 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Swaidani, S. et al. The critical role of epithelial-derived Act1 in IL-17- and IL-25-mediated pulmonary inflammation. J. Immunol. 182, 1631–1640 (2009).

    CAS  PubMed  Article  Google Scholar 

  84. Pancer, Z., Mayer, W. E., Klein, J. & Cooper, M. D. Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey. Proc. Natl Acad. Sci USA 101, 13273–13278 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. Tsang, M., Friesel, R., Kudoh, T. & Dawid, I. Identification of Sef, a novel modulator of FGF signalling. Nature Cell Biol. 4, 165–169 (2002).

    CAS  PubMed  Article  Google Scholar 

  86. Yang, R. B. et al. A novel interleukin-17 receptor-like protein identified in human umbilical vein endothelial cells antagonizes basic fibroblast growth factor-induced signaling. J. Biol. Chem. 278, 33232–33238 (2003).

    CAS  PubMed  Article  Google Scholar 

  87. Xiong, S. et al. hSef inhibits PC-12 cell differentiation by interfering with Ras–mitogen-activated protein kinase MAPK signaling. J. Biol. Chem. 278, 50273–50282 (2003).

    CAS  PubMed  Article  Google Scholar 

  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, 1229–1234 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. Yang, X. et al. Sef interacts with TAK1 and mediates JNK activation and apoptosis. J. Biol. Chem. 279, 38099–38102 (2004).

    CAS  PubMed  Article  Google Scholar 

  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/mitogen-activated protein kinase signaling pathway. Cell Signal. 18, 1287–1298 (2006).

    PubMed  Article  CAS  Google Scholar 

  91. McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nature Rev. Immunol. 7, 429–442 (2007).

    CAS  Article  Google Scholar 

  92. Kikly, K., Liu, L., Na, S. & Sedgwick, J. D. The IL-23/Th17 axis: therapeutic targets for autoimmune inflammation. Curr. Opin. Immunol. 18, 670–675 (2006).

    CAS  PubMed  Article  Google Scholar 

  93. Lubberts, E. IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 41, 84–91 (2008).

    CAS  PubMed  Article  Google Scholar 

  94. Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med 194, 519–527 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Chabaud, M., Lubberts, E., Joosten, L., van Den Berg, W. & Miossec, P. IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis. Arthritis Res. 3, 168–177 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Lubberts, E. et al. IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis. J. Immunol. 167, 1004–1013 (2001).

    CAS  PubMed  Article  Google Scholar 

  97. Murphy, C. A. et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med 198, 1951–1957 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunol. 6, 1123–1132 (2005).

    CAS  Article  Google Scholar 

  99. Langrish, C. L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med 201, 233–240 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Duerr, R. H. et al. A Genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    CAS  Article  PubMed  Google Scholar 

  102. Mangan, P. R. et al. Transforming growth factor-β induces development of the T H17 lineage. Nature 441, 231–234 (2006).

    CAS  Article  PubMed  Google Scholar 

  103. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector T H17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Article  Google Scholar 

  104. Ivanov, I. et al. The orphan nuclear receptor RORγT directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    CAS  PubMed  Article  Google Scholar 

  105. Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med 203, 2271–2279 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).

    CAS  PubMed  Article  Google Scholar 

  108. Zhou, L. et al. IL-6 programs T H-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunol. 8, 967–974 (2007).

    CAS  Article  Google Scholar 

  109. Milner, J. D. et al. Impaired T H17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

Sarah L. Gaffen has received travel reimbursement, honoraria (<US$10,000) and a research grant from Amgen.

Related links

Related links

FURTHER INFORMATION

Sarah L. Gaffen's homepage

Glossary

TH1 and TH2 cells

The two main subsets of activated CD4+ T cells. T helper 1 (TH1) cells produce interferon-γ and tumour necrosis factor, thereby promoting cell-mediated immunity that is mainly directed towards intracellular pathogens. TH2 cells produce interleukin-4 (IL-4), IL-5 and IL-13, 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 interleukin-17A (IL-17A), IL-17F, IL-22, IL-21 and (in humans) IL-26. T helper 17 (TH17) cells promote neutrophil activation and immunity to extracellular pathogens. They also promote inflammation in autoimmunity.

γδ T cell

A T cell that expresses a T cell receptor consisting of a γ-chain and a δ-chain. These T cells are present mainly in the intestinal epithelium as intraepithelial lymphocytes (IELs). Although the exact function of γδ T cells (or IELs) is still unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses mediated by the mucosal immune system.

Lymphoid tissue inducer (LTi) cell

A cell that is present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue (NALT). LTi cells are required for the development of these lymphoid organs. The inductive capacity of these cells for the generation of Peyer's 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

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

Fluorescence resonance energy transfer

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.

Canonical NF-κB pathway

A typical pathway of nuclear factor-κB (NF-κB) activation that involves phosphorylation and degradation of the prototypical NF-κB inhibitor, inhibitor of NF-κB-α (IκBα).

Non-canonical NF-κB pathway

A pathway of nuclear factor-κB (NF-κB) activation that does not involve inhibitor of NF-κB-α (IκBα) degradation but relies on the processing of an NF-κB precursor protein, p100, leading to nuclear translocation of the p52–RELB NF-κB heterodimer.

Toll/IL-1 receptor (TIR) domain

An intracellular signalling domain that is found in interleukin-1 (IL-1) receptor, Toll-like receptors and several adaptor proteins, including MYD88 (myeloid differentiation primary response protein 88).

BB-loop

A structured loop linking the second α-helix and the second β-sheet within Toll/IL-1 receptor (TIR) domains. This loop is a specificity determinant for TIR domains, and certain mutations in the BB-loop cause impairment of Toll-like receptor 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 owing to the presence of AU-rich elements (AREs) located in the 3′ untranslated region. Proteins that bind to AREs target these transcripts to the exosome complex for degradation.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gaffen, S. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 9, 556–567 (2009). https://doi.org/10.1038/nri2586

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri2586

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing