RESEARCH HIGHLIGHTS Nature Reviews Immunology | Published online 23 November 2015; doi:10.1038/nri.2015.2 shown to signal through IL-17RA, of the IL-17 family, whereas IL-17RC Journal club which was also unrelated to other seems to be specific for IL-17 and known cytokine receptors (Yao et al., IL-17F. Nonetheless, there are few IL-17 RECEPTOR COMPOSITION 1995). However, it was unclear how phenotypic differences between mice IL-17RA operated at a molecular level. lacking IL-17RA or IL-17RC, and It has now been a decade since the Toy et al. approached this issue by patients with null mutations in either paradigm-shifting discovery of T helper reconstituting fibroblasts from Il17ra–/– subunit also have remarkably similar 17 (TH17) cells in 2005 forced everyone mice with human IL-17RA. They defects, with their major phenotype working on effector CD4+ T cells to observed that IL-17-induced signalling being chronic mucosal candidiasis reinterpret their findings in the context could only be restored in these (Puel et al., 2011; Ling et al., 2015). of this interleukin-17 (IL-17)-producing fibroblasts upon co-expression of Thus, this important study by Toy et al. TH cell population. We now know that human IL-17RC with human IL-17RA, clarified the constituents of the IL-17 IL-17-induced signalling has a crucial but not upon co-expression of other receptor complex, which set the stage role in immunity to extracellular IL-17R family members. As the Il17ra–/– for a deeper understanding of its microorganisms, particularly to fungal cells expressed endogenous mouse biological activities. pathogens such as Candida albicans. IL-17RC, this finding also revealed an Sarah Gaffen Conversely, IL-17 mediates pathogenic unexpected species-dependent University of Pittsburgh inflammation in several autoimmune interaction between IL-17R subunits School of Medicine, Pittsburgh, Pennsylvania 15261, USA. conditions. The study by Toy et al. in and their ligands, which was confirmed e-mail: [email protected] 2006 marked a major advance in our by co-immunoprecipitation of human The author declares competing interests: understanding of IL-17 signal IL-17RC ... is IL-17RA with human IL-17RC. The see Web version for details. transduction, showing that IL-17 authors then used this system to an obligate ORIGINAL RESEARCH PAPER Toy, D. et al. Cutting receptor C (IL-17RC) is an obligate examine the structure–function edge: interleukin 17 signals through a heteromeric co-receptor with IL-17RA for signalling co-receptor requirements for IL-17RC; they found receptor complex. J. Immunol. 177, 36−39 (2006) induced by IL-17A and IL-17F. not only that IL-17RC is required for FURTHER READING Yao, Z. et al. Herpesvirus with IL-17RA Saimiri encodes a new cytokine, IL-17, which binds IL-17A (commonly known as IL-17) ligand binding but also that the for signalling to a novel cytokine receptor. Immunity 3, 811−821 (1995) | Puel, A. et al. Chronic mucocutaneous is the eponymous cytokine of TH17 cells IL-17RC cytoplasmic tail is essential for and the founding member of a induced by signalling in response to IL-17. candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65−68 (2011) structurally distinct subclass of IL-17A and Since this ground-breaking study, | Ling, Y. et al. Inherited IL-17RC deficiency in cytokines. Both IL-17 and its closest IL-17F IL-17RA has emerged as a common patients with chronic mucocutaneous candidiasis. homologue, IL-17F, had been previously receptor subunit for multiple members J. Exp. Med. 212, 619−631 (2015) NATURE REVIEWS | IMMUNOLOGY www.nature.com/nri © 2015 Macmillan Publishers Limited. All rights reserved.