Human LY9 governs CD4⁺ T cell IFN-γ immunity to Mycobacterium tuberculosis

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_H1*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_H1* cells. T_H1* cells express higher levels of LY9 than other CD4⁺ T cells. Mechanistically, LY9 polarizes naïve CD4⁺ T cells toward memory T_H1* 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_H1*, but not T_H1, 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_H1* cell- and IFN-γ-dependent protective immunity to M.tb in humans.