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Human inherited disorders of interferon-gamma (IFN-γ) 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 kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ 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. These findings suggest that 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-γ. [Display omitted] • X-linked recessive complete human MCTS1 deficiency underlies mycobacterial disease • A lack of MCTS1 inhibits JAK2 translation by impairing ribosome recycling at two uORFs • Decreases in JAK2 protein levels impair the responses of NK and T lymphocytes to IL-23 • Innate-like T cells from patients produce low levels of IFN-γ upon IL-23 stimulation X-linked recessive human MCTS1 deficiency underlies mycobacterial disease by impairing JAK2 translation in innate-like T lymphocytes, thereby decreasing the IL-23-dependent production of IFN-γ by these cells upon mycobacterial challenge. [ABSTRACT FROM AUTHOR]