Inherited Human Itk Deficiency Impairs Ifn-Γ Immunity and Underlies Tuberculosis Publisher Pubmed



Ogishi M^{1, 2} ; Yang R¹ ; Rodriguez R^{3, 4} ; Golec DP⁵ ; Martin E^{3, 4} ; Philippot Q^{4, 6} ; Bohlen J^{4, 6} ; Pelham SJ¹ ; Arias AA^{1, 7, 8} ; Khan T⁹ ; Ata M⁹ ; Ali FA⁹ ; Rozenberg F¹⁰ ; Kong XF¹ Show All Authors
Source: Journal of Experimental Medicine Published:2023

Abstract

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. © 2022 Ogishi et al.