Human MCTS1-dependent translation reinitiation is essential for IFN-g immunity to mycobacteria

Human inherited disorders of IFN-g immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the cytosolic kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 translation is sufficiently low to impair cellular responses to IL-23 and, to a lesser extent, IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 selectively impair the production of IFN-g by innate-like MAIT and gd adaptive T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-g.