Ogishi, MasatoYang, RuiRodriguez, RemyGolec, Dominic P.Martin, EmmanuelPhilippot, QuentinBohlen, Jonathan2024-02-232024-02-2320220022-10071540-9538https://doi.org/10.1084/jem.20220484https://hdl.handle.net/20.500.12452/13302Inborn errors of IFN-gamma immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4(+) alpha beta T lymphocytopenia with a concomitant expansion of CD4(-)CD8(-) double-negative (DN) alpha beta and V delta 2(-) gamma delta T lymphocytes, both displaying a unique CD38(+)CD45RA(+)T-bet(+)EOMES(-) phenotype. Itk-deficient mice recapitulated an expansion of the gamma delta T and DN alpha beta T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-gamma in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-gamma, and CD4(+), CD8(+), DN alpha beta T, V delta 2(+) gamma delta T, and MAIT cells display impaired IFN-gamma production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-gamma-producing T cell subsets, thereby underlying TB.eninfo:eu-repo/semantics/openAccess[Keyword Not Available]Article2201363266972-s2.0-85146519678Q1WOS:001062493400001Q110.1084/jem.20220484