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.
Ogishi, Masato; Yang, Rui; Rodriguez, Rémy; Golec, Dominic P; Martin, Emmanuel; Philippot, Quentin; Bohlen, Jonathan; Pelham, Simon J; Arias, Andrés Augusto; Khan, Taushif; Ata, Manar; Al Ali, Fatima; Rozenberg, Flore; Kong, Xiao-Fei; Chrabieh, Maya; Laine, Candice; Lei, Wei-Te; Han, Ji Eun; Seeleuthner, Yoann; Kaul, Zenia; Jouanguy, Emmanuelle; Béziat, Vivien; Youssefian, Leila; Vahidnezhad, Hassan; Rao, V Koneti; Neven, Bénédicte; Fieschi, Claire; Mansouri, Davood; Shahrooei, Mohammad; Pekcan, Sevgi; Alkan, Gulsum; Emiroğlu, Melike; Tokgöz, Hüseyin; Uitto, Jouni; Hauck, Fabian; Bustamante, Jacinta; Abel, Laurent; Keles, Sevgi; Parvaneh, Nima; Marr, Nico; Schwartzberg, Pamela L; Latour, Sylvain; Casanova, Jean-Laurent; and Boisson-Dupuis, Stéphanie, "Inherited Human ITK Deficiency Impairs IFN-γ Immunity and Underlies Tuberculosis" (2023). Department of Dermatology and Cutaneous Biology Faculty Papers. Paper 173.
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