IMMUNODEFICIENCIES. 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 ? (IFN ?) 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? and ROR?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? and ROR?T deficient individuals also displayed an impaired IFN ? response to Mycobacterium. This principally reflected profoundly defective IFN ? production by circulating ?d T cells and CD4(+)CCR6(+)CXCR3(+) aß T cells. In humans both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require ROR? ROR?T or both.