Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis

Inborn errors of IFN-γ 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⁺ αβ T lymphocytopenia with a concomitant expansion of CD4⁻CD8⁻ double-negative (DN) αβ and Vδ2⁻ γδ T lymphocytes, both displaying a unique CD38⁺CD45RA⁺T-bet⁺EOMES⁻ phenotype. Itk-deficient mice recapitulated an expansion of the γδ TandDNαβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients’ T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients’ total lymphocytes secrete small amounts of IFN-γ, and CD4⁺, CD8⁺,DNαβ T, Vδ2⁺ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ–producing T cell subsets, thereby underlying TB.