Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations

Satoshi Okada, Janet G Markle, Elissa K Deenick, Federico Mele, Dina Averbuch, Macarena Lagos, Mohammed Alzahrani, Saleh Zaid Al-Muhsen, Rabih Halwani, Cindy S Ma, Natalie Wong, Claire Soudais, Lauren A Henderson, Hiyam Marzouqa, Jamal Shamma, Marcela Gonzalez, Ruben Martinez-Barricarte, Chizuru Okada, Danielle T Avery, Daniela LatorreCaroline Deswarte, Fabienne Jabot-Hanin, Egidio Torrado, Jeffrey Fountain, Aziz Belkadi, Yuval Itan, Bertrand Boisson, Melanie Migaud, Cecilia S Lindestam Arlehamn, Alessandro Sette, Sylvain Breton, James McCluskey, Jamie Rossjohn, Jean-Pierre de Villartay, Despina Moshous, Sophie Hambleton, Sylvain Latour, Peter D Arkwright, Capucine Picard, Olivier Lantz, Dan Engelhard, Masao Kobayashi, Laurent Abel, Andrea M Cooper, Luigi D Notarangelo, Stephanie Boisson-Dupuis, Anne Puel, Federica Sallusto, Jacinta Bustamante, Stuart G Tangye, Jean-Laurent Casanova

Research output: Contribution to journalArticleResearchpeer-review

247 Citations (Scopus)


Human inborn errors of immunity mediated by the cytokines interleukin-17A/F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-gamma (IFN-gamma) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORgamma and RORgammaT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORgamma- and RORgammaT-deficient individuals also displayed an impaired IFN-gamma response to Mycobacterium. This principally reflected profoundly defective IFN-gamma production by circulating gammadelta T cells and CD4+CCR6+CXCR3+ alphabeta T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORgamma, or RORgammaT, or both.
Original languageEnglish
Pages (from-to)606 - 613
Number of pages8
Issue number6248
Publication statusPublished - 2015

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