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

Masato Ogishi , Rui Yang , Rémy Rodriguez (1) , Dominic Golec , Emmanuel Martin , Quentin Philippot , Jonathan Bohlen , Simon Pelham , Andrés Augusto Arias , Taushif Khan , Manar Ata , Fatima Al Ali , Flore Rozenberg , Xiao-Fei Kong , Maya Chrabieh , Candice Laine , Wei-Te Lei , Ji Eun Han , Yoann Seeleuthner , Zenia Kaul , Emmanuelle Jouanguy , Vivien Béziat , Leila Youssefian , Hassan Vahidnezhad , V. Koneti Rao , Bénédicte Neven , Claire Fieschi , Davood Mansouri , Mohammad Shahrooei , Sevgi Pekcan , Gulsum Alkan , Melike Emiroğlu , Hüseyin Tokgöz , Jouni Uitto , Fabian Hauck , Jacinta Bustamante , Laurent Abel , Sevgi Keles , Nima Parvaneh , Nico Marr , Pamela Schwartzberg , Sylvain Latour , Jean-Laurent Casanova , Stéphanie Boisson-Dupuis

1 Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm UMR 1163

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 T and DN αβ 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+, DN αβ 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.

Domaines: Sciences du Vivant [q-bio]

Masato Ogishi, Rui Yang, Rémy Rodriguez, Dominic Golec, Emmanuel Martin, et al.. Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis. Journal of Experimental Medicine, 2023, 220 (1), ⟨10.1084/jem.20220484⟩. ⟨hal-03864121⟩