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

We report the recessive, complete deficiency of the human lymphocytic surface receptor LY9 (SLAMF3, CD229) as a genetic determinant of tuberculosis (TB). Only patients with TB have LY9 deficiency, which is not seen in patients with any other infectious disease studied, including other mycobacterial diseases. The patients' lymphocytes neither express LY9 nor respond to LY9 crosslinking. Human LY9 polarizes TCR-primed naive CD4+ T cells towards effector CD4+ TH1 cells by inducing T-bet via SAP and ROR without SAP. LY9 then augments Mycobacterium-induced IFN production via NFAT1 and RORT in a TH1 cell-intrinsic manner and in cis. LY9 is dispensable for the development of myeloid and lymphoid leukocyte subsets other than TH1 cells and the production of IFN-gamma by TH1, CD8+ T, T, MAIT, iNKT, and NK lymphocytes. Human LY9 is thus required for optimal CD4+ TH1 cell IFN immunity, the inefficiency of which predisposes to TB.