Human LY9 governs CD4$^+$T cell IFN-γ immunity to Mycobacterium tuberculosis
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2025-05
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Journal Article
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Abstract
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 (T$_H$1*cell) memory phenotype. We report that autosomal recessive deficiency of the human lymphocytic surface receptor LY9 (SLAMF3 and CD229), which is found in less than 10$^{-5}$ individuals in the general population, underlies TB in three unrelated patients due to selective impairment in IFN-γ production by T$_H$1* cells. T$_H$1* cells express higher levels of LY9 than other CD4$^+$ T cells. Mechanistically, LY9 polarizes naïve CD4$^+$T cells toward memory T$_H$1* cells by inducing T-bet via signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) and RORγT (thymus-specific retinoid-related orphan receptor γ) without SAP. LY9 costimulation enhances TCR-driven IFN-γ production of memory T$_H$1*, but not T$_H$1, cells in a T cell-intrinsic manner via NFAT1 (nuclear factor of activated T cells 1) and RORγT. LY9 is likely to govern an optimal T$_H$1* cell- and IFN-γ-dependent protective immunity to M.tb in humans.
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10 (107)
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AAAS
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09604 - Sallusto, Federica / Sallusto, Federica