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

Abstract

Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function <i>IL23R</i> variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and <i>Mycobacterium</i>-inducible IFN-γ immunity in both Vδ2⁺ γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F-dependent immunity to <i>Candida</i> in a single lymphocyte subset but is required for IFN-γ-dependent immunity to <i>Mycobacterium</i> in at least two lymphocyte subsets.