Impairment of IL-17 Immunity to Candida and IFN-g Immunity to Mycobacterium in Humans with Bi-Allelic Rorc mutations

Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis (CMC), which is characterized by infections of the skin, nails, oral and genital mucosae with Candida albicans. Inborn errors of human IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD), a rare congenital disorder characterized by susceptibility to infections by poorly virulent intracellular pathogens such as Mycobacterium bovis Bacille Calmette-Guérin vaccines (BCG) and non-tuberculosis Mycobacterium. Rarely, patients may be affected by both candidiasis and mycobacteriosis, including some patients with IL-12p40 and IL-12Rβ1 deficiencies that impair IFN-γ immunity and IL-17 immunity. We studied seven patients from three unrelated consanguineous kindreds with this unusual combination of infectious diseases without known genetic disorder. We combined whole exome sequencing and genome wide linkage analysis, and discovered bi-allelic loss-of-function mutations in RORC, which encodes the transcription factors RORγ and RORγT. All of the seven patients suffered from severe mycobacterial infections, and six also exhibited mild CMC. RORγT is the key transcription factor of Th17 cells, which produce IL-17 and IL-22. Therefore, as predicted by the mouse model, RORγT deficiency prevented the development of IL-17-producing T cells, which accounts for the patients' CMC. Consistent with the phenotype of Rorc^-/- mice, these patients presented with mild T cell lymphopenia, small thymus, lack of palpable axillary and cervical lymph nodes, and absence of MAIT and iNKT cells.

The patients' severe infections with mycobacteria were not predicted by previous studies of Rorc^-/- mice. To explain this unexpected phenotype, we focused on IFN-γ immunity. Leukocytes from RORC^-/- patients showed impaired IFN-γ production in response to a mycobacterial challenge, and this defect is probably attributable to the functional impairment of CD4⁺ CCR6⁺ CXCR3⁺ αβ T cells, γδT cells, or both. These findings also suggested that IFN-γ treatment may be beneficial for RORC^-/- patients. Moreover, this phenotype does not seem to be human-specific, as we also found that Rorc^-/- mice deficient were susceptible to mycobacterial infection. We thus discovered that human RORC is essential not only for the development of IL-17-producing lymphocytes protecting the mucocutaneous barriers against Candida, but also for the activation of IFN-g-producing T cells, and for systemic protection against Mycobacterium.