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The Journal of Experimental MedicineGeneticsPeer-reviewed journal article

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

Diana Olguín-CalderóniD, Laura E. KilpatrickiD, Clément ConiliD, Quentin PhilippotiD, Masato OgishiiD, Joseph VellutiniiD, Ji Eun HaniD, Narelle KeatingiD, Hailun LiiD, Geetha RaoiD, Jonathan BohleniD, Charles S. LayiD, Simon PlattiD, Gaspard KerneriD, Elsa FeredjiD, Jessica N. PeeliD, Mana MomenilandiiD, Yoann SeeleuthneriD, Candice LainéiD, Camille SoudéeiD, Claire LeloupiD, C. Debuisson, Fanny LanternieriD, Samuel BitouniD, Stéphan PavyiD, , Stéphanie Boisson‐DupuisiD

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Abstract

Homozygosity for rare loss-of-function IL23R variants abolishes IL-23-dependent IFN-{gamma} production by lymphocytes, including NK and innate-like T cells, thereby underlying clinical disease due to weakly virulent mycobacterial species. We report selective enrichment in homozygosity for four hypomorphic IL23R variants in our cohort of patients with tuberculosis. Three of these IL23R alleles are rare (G300V, G149R, and L372F), with a minor allele frequency (MAF) under 1%, but the fourth (R381Q) is surprisingly common, with an MAF as high as 10.2% in certain populations. The other 15 missense alleles found in the homozygous state in public databases are isomorphic. The four hypomorphic IL-23R variants identified dimerize with IL-12R{beta}1 and bind IL-23. However, their function is impaired by low levels of cell surface expression (R381Q, G300V) and/or as a consequence of conformational changes altering agonist efficacy. IFN-{gamma} production in response to IL-23 is impaired in innate-like T cells and NK cells. These data suggest that recessive partial IL-23R deficiency, whether due to rare or common variants, confers a predisposition to tuberculosis while preserving immunity to less virulent mycobacteria. One sentence summaryHomozygous hypomorphic IL23R variants impair IL-23-dependent IFN-{gamma} production and underlie tuberculosis.

In-depth summary

Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (13 Aug 2026) · CC BY 4.0

Homozygosity for hypomorphic IL23R variants (G149R, G300V, R381Q) partly impairs IL-23-dependent IFN-γ production in patient cells; with L372F (effect inferred), they are enriched in tuberculosis, not MSMD or CMC patients.

Complete IL-23R deficiency causes Mendelian susceptibility to mycobacterial diseases (MSMD), and homozygosity for the common TYK2 P1104A allele is enriched in tuberculosis (TB). The authors tested whether other biallelic IL23R variants, rare or common, underlie MSMD or TB, and found that partial deficiency tracks with TB.

Key results

  1. ShownAn overexpression screen of 19 non-LOF-annotated biallelic IL23R variants found 15 isomorphic and four hypomorphic ones (G300V, R381Q, G149R, L372F), while C115Y was LOF.

    Cohort of 24,046 patients (1,874 TB, 901 MSMD) plus public databases; HEK293T luciferase assay with hypomorphs at ≤50% of WT activity; pSTAT3 western blots were lower for the same four variants. · Four hypomorphic biallelic IL23R variants; Figure legends

  2. SuggestedThe data suggest the hypomorphs act through reduced surface expression and/or receptor conformation rather than lower IL-23 affinity.

    Surface expression of G300V and R381Q was weaker than WT (similar to C115Y); G149R and L372F matched WT. NanoBRET affinities were similar to WT for all four, but maximum signals were lower (WT heterodimer KD = 27.0 pM). · The IL-23R mutants have low levels of cell…; Figure legends

  3. ShownPatient cells homozygous for G149R, G300V or R381Q show impaired but not abolished IL-23 signalling and IFN-γ induction, mainly in MAIT, Vδ2+ γδ T and NK cells; R381Q is milder.

    EBV-B cells from 3 G300V, 5 R381Q and 2 G149R homozygotes; scRNA-seq IFNG induction after IL-23 reduced; BCG-stimulated IFN-γ reduced; PMA/ionomycin responses similar across genotypes. · Impaired IL-23 signaling in lymphoid cell lines…; Impaired IL-23–mediated IFNG mRNA induction in…; Impaired ex vivo IL-23–mediated induction of…; Homozygosity for IL23R hypomorphic variants…

  4. ShownHomozygosity for hypomorphic IL23R variants is enriched among TB patients but not MSMD or CMC patients; the absence of heterozygote enrichment suggests recessive inheritance.

    G300V homozygote proportion 2.1 × 10^−3 in 1,874 TB cases vs 4.8 × 10^−5 in 20,883 controls (OR 26.5 [4.2–167.0], P = 4.9 × 10^−4). Activity-weighted burden test P = 3.8 × 10^−2; Middle Eastern subset P = 9.7 × 10^−5; 15 isomorphic variants P = 0.48. · Enrichment in homozygosity for hypomorphic IL23R…; Variant enrichment analysis

  5. ClaimedR381Q is common and G300V is rare. The authors propose that R381Q was under negative selection in Europeans, probably linked to TB burden.

    R381Q gnomAD v4.1.0 frequency 5.4%, with 2,839 homozygotes (0.4%). G300V common ancestor about 3,078 years ago (95% CI 972–11,500). R381Q frequency fell from 15% (Neolithic) and 10% (Bronze age) to 5.5% today. · Population genetics of IL23R; Discussion; Detection of founder effect

Methods, data and reproducibility

Biallelic IL23R variants were screened in a large infection cohort and public databases. They were tested in HEK293T overexpression assays and in patient-derived cells (EBV-B, T blasts, PBMCs; flow cytometry, scRNA-seq). Recessive-model association tests were run with regenie.

  • In-house HGID cohort of patients with infectious diseases, including TB and MSMD patients · human · n = 24,046 patients (1,874 TB, 901 MSMD); 20,883 controls
  • Public population databases for biallelic IL23R variants (gnomAD v4.1.0, ATAVDB, Great Middle East, Iranome, Turkish Variome, BRAVO) · human
  • EBV-B cell lines from controls and IL23R homozygous patients · human · n = 8 controls, 3 G300V, 5 R381Q, 2 G149R, 2 C115Y
  • scRNA-seq of PBMCs, baseline and IL-23 stimulated 6 h · human · n = Baseline: 11 controls, 15 patients; stimulated: 9 controls, 11 patients · PRJNA1449438
Methods & tools
regenie, Plink v1.9, EstiAge, Seurat, muscat, DESeq2, apeglm, fgsea, limma, gnomAD v4.1, CADD v1.7, GraphPad Prism
Reagents & environment
Plink v1.9; GraphPad Prism v8.4.3, v10.5.0 and v10.1.0; gnomAD v4.1; CADD v1.7. No container or requirements file stated.
Reproducibility gaps
No analysis code link given; other data are stated to be in the article and its supplement. Patient-level data availability beyond scRNA-seq is not described.
Limitations (4)
  • No L372F homozygotes exist in the in-house cohort (more than 24,000 individuals), so the effect of that genotype could not be tested in patient cells. · stated by the authors
  • Differences in disease onset and extrapulmonary TB between G300V and R381Q homozygotes rest on a limited number of individuals. · stated by the authors
  • Many controls live in regions with low to moderate TB prevalence and were probably not exposed to M. tuberculosis, so the TB risk is probably underestimated. · stated by the authors
  • Rare genotypes rest on very few people (G300V enrichment on five homozygotes in two Turkish families; 1 to 3 individuals in several functional assays), giving a wide OR confidence interval. · noted in this summary

Read this if you work on inborn errors of immunity, IL-23/IFN-γ biology or mycobacterial disease genetics, or on recessive burden tests for hypomorphic variants.

Citations
1
FWCI
2.68
Field percentile
top 9%

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