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

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (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 ROR gamma and ROR gamma T isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from ROR gamma- and ROR gamma T-deficient individuals also displayed an impaired IFN-gamma response to Mycobacterium. This principally reflected profoundly defective IFN-gamma production by circulating gamma delta T cells and CD4+CCR6+CXCR3+ alpha beta T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require ROR gamma, ROR gamma T, or both.