Homozygosity for rare or common hypomorphic IL23R variants confers a predisposition to tuberculosis in humans
Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-Gproduction by lymphocytes, including NK and innate-like T cells, thereby underlying clinicaldisease due to weakly virulent mycobacterial species. We report selective enrichment inhomozygosity for four hypomorphic IL23R variants in our cohort of patients withtuberculosis. Three of these IL23R alleles are rare (G300V, G149R and L372F), with a minorallele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with aMAF as high as 10.2% in certain populations. The other 15 missense alleles found in thehomozygous state in public databases are isomorphic. The four hypomorphic IL-23R variantsidentified dimerize with IL-12RB1 and bind IL-23. However, their function is impaired bylow levels of cell-surface expression (R381Q, G300V) and/or as a consequence ofconformational changes altering agonist efficacy. IFN-G production in response to IL-23 isimpaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23Rdeficiency, whether due to rare or common variants, confers a predisposition to tuberculosiswhile preserving immunity to less virulent mycobacteria.