Human IL23 is essential for IFN-g dependent immunity to mycobacteria

Patients with autosomal recessive IL12p40 or IL12RB1 deficiency display Mendelian susceptibility to mycobacterial disease due to impaired IFNg production and, less commonly, chronic mucocutaneous candidiasis due to impaired IL17AF production. We report six patients from four kindreds with AR IL23R deficiency. These patients are homozygous for one of four different loss of function IL23R variants. All six patients have a history of MSMD but only two suffered from CMC. We show that IL23 induces IL17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL23. By contrast, IL23 is required for both baseline and Mycobacterium inducible IFNg immunity in both Vd2 T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL23 appears to contribute to IL17AF dependent immunity to Candida in a single lymphocyte subset, but is required for IFNg dependent immunity to Mycobacterium in at least two lymphocyte subsets.