IL-17RC ... is an obligate co-receptor with IL-17RA for signalling induced by IL-17A and IL-17F
It has now been a decade since the paradigm-shifting discovery of T helper 17 (TH17) cells in 2005 forced everyone working on effector CD4+ T cells to reinterpret their findings in the context of this interleukin-17 (IL-17)-producing TH cell population. We now know that IL-17-induced signalling has a crucial role in immunity to extracellular microorganisms, particularly to fungal pathogens such as Candida albicans. Conversely, IL-17 mediates pathogenic inflammation in several autoimmune conditions. The study by Toy et al. in 2006 marked a major advance in our understanding of IL-17 signal transduction, showing that IL-17 receptor C (IL-17RC) is an obligate co-receptor with IL-17RA for signalling induced by IL-17A and IL-17F.
IL-17A (commonly known as IL-17) is the eponymous cytokine of TH17 cells and the founding member of a structurally distinct subclass of cytokines. Both IL-17 and its closest homologue, IL-17F, had been previously shown to signal through IL-17RA, which was also unrelated to other known cytokine receptors (Yao et al., 1995). However, it was unclear how IL-17RA operated at a molecular level.
Toy et al. approached this issue by reconstituting fibroblasts from Il17ra−/− mice with human IL-17RA. They observed that IL-17-induced signalling could only be restored in these fibroblasts upon co-expression of human IL-17RC with human IL-17RA, but not upon co-expression of other IL-17R family members. As the Il17ra−/− cells expressed endogenous mouse IL-17RC, this finding also revealed an unexpected species-dependent interaction between IL-17R subunits and their ligands, which was confirmed by co-immunoprecipitation of human IL-17RA with human IL-17RC. The authors then used this system to examine the structure–function requirements for IL-17RC; they found not only that IL-17RC is required for ligand binding but also that the IL-17RC cytoplasmic tail is essential for signalling in response to IL-17.
Since this ground-breaking study, IL-17RA has emerged as a common receptor subunit for multiple members of the IL-17 family, whereas IL-17RC seems to be specific for IL-17 and IL-17F. Nonetheless, there are few phenotypic differences between mice lacking IL-17RA or IL-17RC, and patients with null mutations in either subunit also have remarkably similar defects, with their major phenotype being chronic mucosal candidiasis (Puel et al., 2011; Ling et al., 2015). Thus, this important study by Toy et al. clarified the constituents of the IL-17 receptor complex, which set the stage for a deeper understanding of its biological activities.
References
Toy, D. et al. Cutting edge: interleukin 17 signals through a heteromeric receptor complex. J. Immunol. 177, 36–39 (2006)
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author has received travel reimbursements and honoraria from Amgen (location of the authors of Toy et al., 2006).
Related links
Related links
Related links in Nature Research
Rights and permissions
About this article
Cite this article
Gaffen, S. IL-17 receptor composition. Nat Rev Immunol 16, 4 (2016). https://doi.org/10.1038/nri.2015.2
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri.2015.2
This article is cited by
-
Expressions of IL-17 and TNF-α in patients with Hashimoto’s disease combined with thyroid cancer before and after surgery and their relationship with prognosis
Clinical and Translational Oncology (2020)
-
Variants in the IL17 pathway genes are associated with atopic asthma and atopy makers in a South American population
Allergy, Asthma & Clinical Immunology (2019)
-
Gut Microbiota and IL-17A: Physiological and Pathological Responses
Probiotics and Antimicrobial Proteins (2019)