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Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria


Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αβ T, and CD4+ αβ TH1∗ cells unable to compensate for this deficit.

Type Journal
Authors Rui Yang, Federico Mele, Lisa Worley, David Langlais, Jeremie Rosain, Ibithal Benhsaien, Houda Elarabi, Carys A. Croft, Jean-Marc Doisne, Peng Zhang, Marc Weisshaar, David Jarrossay, Daniela Latorre, Yichao Shen, Jing Han, Conor Gruber, Janet Markle, Fatima Al Ali, Mahbuba Rahman, Taushif Khan, Yoann Seeleuthner, View ORCID ProfileGaspard Kerner, Lucas T. Husquin, Julia L. Maclsaac, Mohamed Jeljeli, Fatima Ailal, Michael S. Kobor, Carmen Oleaga-Quintas, Manon Roynard, Mathieu Bourgey, Jamila El Baghdadi, Stephanie Boisson-Dupuis, Anne Puel, Frederic Batteux, Flore Rozenberg, Nico Marr, Qiang Pan-Hammarstrom, Dusan Bogunovic, Lluis Quintana-Murci, Thomas Carroll, Cindy S Ma, Laurent Abel, Aziz Bousfiha, James P. Di Santo, Laurie H Glimcher, Philippe Gros, Stuart G Tangye, Federica Sallusto, Jacinta Bustamante, Jean-Laurent Casanova
Responsible Garvan Author Prof Stuart Tangye
Publisher Name CELL
Published Date 2020-12-31
Published Volume 183
Published Issue 7
Published Pages 1826-1847 e31
Status Published in-print
DOI 10.1016/j.cell.2020.10.046.
URL link to publisher's version