Common and rare IL-23R variants raise tuberculosis risk

Tuberculosis remains a stubborn infection in which some people develop disease despite similar exposures. A new genetic study led by Stéphanie Boisson-Dupuis focused on variants in the IL-23R gene to understand why certain individuals are more susceptible. The team identified four hypomorphic IL-23R variants — G300V, G149R, L372F and R381Q — present in the homozygous state in people and public databases. Three of these alleles (G300V, G149R and L372F) are rare, each with a minor allele frequency (MAF) under 1%, while the fourth, R381Q, is unexpectedly common, reaching a MAF as high as 10.2% in some populations. The study also notes that another 15 missense IL-23R alleles seen homozygous in public databases are isomorphic, meaning they do not alter function in the same way. By examining how these specific IL-23R variants behave, the researchers set out to link gene variation to immune pathway dysfunction and the clinical observation of tuberculosis in otherwise unexplained cases.

The researchers tested the biochemical and cellular consequences of the four hypomorphic IL-23R variants. They found that all four variants can still dimerize with IL-12Rβ1 and bind the IL-23 ligand, indicating that basic receptor assembly and ligand recognition remain intact. Despite this, receptor function was impaired: two variants, R381Q and G300V, showed low levels of cell-surface expression, and other variants caused conformational changes that reduced agonist efficacy. Functionally, this translated into defective production of IFN-γ in response to IL-23 stimulation in innate-like T cells and NK cells, cell types important for early defense against mycobacteria. Putting these results together, the data support a model of recessive partial IL-23R deficiency — whether caused by rare or surprisingly common variants — that specifically undermines IL-23-dependent IFN-γ responses. Importantly, the impairment appears to predispose to tuberculosis while preserving immunity to less virulent mycobacteria, as reported in the study.

The findings clarify a genetic route to tuberculosis susceptibility tied to partial loss of IL-23R function. Because R381Q can be relatively common in some populations, the work highlights that even common variants, when homozygous and hypomorphic, can have meaningful effects on key immune pathways such as IL-23-driven IFN-γ production. By showing that the variants dimerize with IL-12Rβ1 and bind IL-23 yet still fail to trigger adequate IFN-γ from innate-like T cells and NK cells, the study narrows the defect to receptor expression and agonist efficacy rather than complete loss of ligand binding. The authors frame this as recessive partial IL-23R deficiency that underlies tuberculosis risk but spares defense against milder mycobacterial exposures. Overall, the work provides a focused molecular explanation for why some people develop tuberculosis and points to IL-23R biology as a critical determinant of human anti-mycobacterial immunity.