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Ogishi M, Puchan J, Yang R, Arias AA, Han JE, Nguyen T, Gutiérrez-Cózar R, Conil C, Seeleuthner Y, Rinchai D, Zhang P, Ponsin K, Chaldebas M, Feng Y, Neehus AL, Delmonte OM, Khan T, Landegren N, Eriksson D, Bohlen J, Peel JN, Fagniez I, Pelham SJ, Lei WT, Chrabieh M, Laine C, Ouair H, Benhsaien I, Abid A, Abderrhamani Ghorfi I, Souhi H, Ouazzani H, Aniss R, Riminton DS, Kämpe O, Turvey SE, Marr N, Notarangelo LD, Hatipoglu N, Bousfiha A, Ozcelik T, El Baghdadi J, Cobat A, Ma CS, Abel L, Puel A, Bustamante J, Engel P, Gros P, Tangye SG, Sallusto F, Boisson-Dupuis S, Casanova JL
Sci Immunol 10 (107) eads7377 [2025-05-30; online 2025-05-30]
CD4+ T cells are indispensable for optimal immunity to Mycobacterium tuberculosis (M.tb), a pathogen that triggers tuberculosis (TB) in humans. M.tb-specific human CD4+ T cells are known to polarize toward an interferon-γ (IFN-γ)-producing, CCR4-CCR6+CXCR3+T-bet+RORγT+ T helper 1* cell (TH1*cell) memory phenotype. We report that autosomal recessive deficiency of the human lymphocytic surface receptor LY9 (SLAMF3 and CD229), which is found in less than 10-5 individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by TH1* cells. TH1* cells express higher levels of LY9 than other CD4+ T cells. Mechanistically, LY9 polarizes naïve CD4+ T cells toward memory TH1* cells by inducing T-bet via signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) and RORγT (thymus-specific retinoid-related orphan receptor γ) without SAP. LY9 costimulation enhances TCR-driven IFN-γ production of memory TH1*, but not TH1, cells in a T cell-intrinsic manner via NFAT1 (nuclear factor of activated T cells 1) and RORγT. LY9 is likely to govern an optimal TH1* cell- and IFN-γ-dependent protective immunity to M.tb in humans.
Autoimmunity and Serology Profiling [Service]
PubMed 40446017
DOI 10.1126/sciimmunol.ads7377
Crossref 10.1126/sciimmunol.ads7377