Human LY9 governs CD4<sup>+</sup> T cell IFN-γ immunity to <i>Mycobacterium tuberculosis</i>

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.