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.
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.
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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).
Sarah L. Gaffen has received travel reimbursement, honoraria (<US$10,000) and a research grant from Amgen.
- 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).
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.
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Gaffen, S. Structure and signalling in the IL-17 receptor family. Nat Rev Immunol 9, 556–567 (2009). https://doi.org/10.1038/nri2586
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