Humans homozygous for rare or common hypomorphic IL23R variants are prone to tuberculosis.

Summary

Homozygosity for four hypomorphic IL23R variants—including the relatively common R381Q—was enriched among tuberculosis patients. These variants retain IL-23 binding with IL-12Rβ1 dimerization but show reduced surface expression and/or agonist efficacy, leading to impaired IL‑23–induced IFN‑γ production by innate-like T and NK cells and increased TB susceptibility.

Key Findings

• Homozygosity for four hypomorphic IL23R variants (G300V, G149R, L372F, and common R381Q) was selectively enriched in tuberculosis patients.
• Variants dimerized with IL‑12Rβ1 and bound IL‑23 but had reduced cell surface expression (R381Q, G300V) and/or altered agonist efficacy, impairing signaling.
• IL‑23–induced IFN‑γ production by innate-like T cells and NK cells was diminished, supporting recessive partial IL‑23R deficiency as a TB predisposition factor.

Clinical Implications

Genetic screening for hypomorphic IL23R alleles and functional assessment of IL‑23/IFN‑γ pathways could identify individuals at higher TB risk; adjunctive strategies to boost IL‑23–dependent IFN‑γ responses in innate-like lymphocytes may merit exploration.

Limitations

• Cohort size and demographic composition are not specified in the abstract, limiting population-level effect size estimation.
• Comparisons to public databases may be influenced by ancestry differences and database ascertainment.

Future Directions

Define population-attributable risk of IL23R hypomorphic homozygosity across ancestries; assess whether targeted augmentation of IL‑23/IFN‑γ signaling improves host resistance to M. tuberculosis.