Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria

Abstract

Patients with autosomal recessive (AR) IL-12p40 or IL-12RB1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-g production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four unrelated kindreds with AR IL-23R deficiency. All six patients have a history of MSMD but only two suffered from CMC. The four IL23R variants are associated with IL-23R loss of function, both in an isogenic overexpression assay and in the patients’ derived cells. We observe that IL-23R deficiency impairs baseline IFN-g immunity in at least 19 leukocyte subsets, including lymphoid and myeloid subsets, in vivo, without affecting their development per se. After IL-23 stimulation, we observe IFN-g induction in innate-like adaptive (MAIT, Vd2+ gd T) and innate (NK) lymphocytes in healthy controls but not in IL-23R-deficient patients, suggesting that IL-23 act as an early IFN-g-inducing cytokine in these cells, which, in turn, induce IFN-g-dependent transcriptional programs in both lymphoid and myeloid leukocyte subsets. Upon mycobacterial infection ex vivo, we find impaired IFN-g production by IL-23R-deficient MAIT and Vd2+ gd T cells, and to a lower extend in IL-23R-deficient CD4+ T cells. IL-23 is thus required for both baseline and Mycobacterium-inducible IFN-g immunity in at least MAIT and Vd2+ gd T cells, probably contributing to the complete penetrance of MSMD in IL-23R-deficient patients. MAIT cells from IL-23R-deficient patients display impaired IL-17A induction upon IL-23 stimulation, and PBMCs from IL-23R-deficient patients display impaired IL-17A/F production in response to heat-killed C. albicans, probably accounting for their risk of CMC. We observe normal development of Mycobacterium- and C. albicans-specific CD4+ memory T cells in IL-23R-deficient patients, possibly accounting for the absence of mycobacterial disease recurrence and the incomplete penetrance of CMC in these patients, respectively. Overall, our findings suggest that human IL-12 and IL-23 are functionally more closely related, via their induction of IFN-g, than previously thought based on the classical TH1/TH17 paradigm established in mice. They further suggest that the mechanisms underlying the therapeutic efficacy of IL-23p19 blockers may involve an inhibition, not only of excessive IL-17 immunity, but also of excessive IFN-g immunity.