ABSTRACT: CD4+ T cells are indispensable for optimal immunity to Mycobacterium tuberculosis (M.tb), a virulent pathogen that triggers tuberculosis (TB), in humans, as evidenced by studies of patients with CD4+ T lymphocytopenia. M.tb-specific human CD4+ T cells are known to polarize toward an IFN-γ-producing, T-bet+RORγT+ TH1* memory phenotype. We report that inherited deficiency of the human lymphocytic surface receptor LY9 (SLAMF3, CD229) underlies TB, but not BCG disease, due to dysfunction of TH1* cells. We find autosomal recessive, complete LY9 deficiency in three unrelated patients with TB and one asymptomatic relative, but not in patients with other infections studied, including patients with BCG disease, and in less than 10-5 individuals in the general population. TH1* cells in LY9-deficient individuals show selective impairment in IFN-γ production. By contrast, LY9 deficiency does not disrupt the development or function of leukocyte subsets other than TH1* cells, including TH1 cells. Mechanistically, LY9 polarizes naïve CD4+ T cells toward memory TH1* cells by inducing T-bet via SAP, and RORγT without SAP. Among CD4+ T cell subsets, TH1* cells express LY9 at the highest level. Finally, LY9 costimulation enhances TCR-driven IFN-γ production of memory TH1*, but not TH1, cells in a T-cell-intrinsic manner via NFAT1 and RORγT. Human LY9 is thus required for an optimal TH1*-cell- and IFN-γ-dependent protective immunity to M.tb. These findings, in turn, suggest that, without fully functional TH1* cells, TH1 cells and other T cell subsets may not be sufficient for optimal protective immunity to M.tb in humans.
