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

Rui Yang, Federico Mele, Lisa Worley, David Langlais, Jérémie Rosain, Ibithal Benhsaien, Houda Elarabi, Carys A. Croft, Jean Marc Doisne, Peng Zhang, Marc Weisshaar, David Jarrossay, Daniela Latorre, Yichao Shen, Jing Han, Masato Ogishi, Conor Gruber, Janet Markle, Fatima Al Ali, Mahbuba RahmanTaushif Khan, Yoann Seeleuthner, Gaspard Kerner, Lucas T. Husquin, Julia L. Maclsaac, Mohamed Jeljeli, Abderrahmane Errami, Fatima Ailal, Michael S. Kobor, Carmen Oleaga-Quintas, Manon Roynard, Mathieu Bourgey, Jamila El Baghdadi, Stéphanie Boisson-Dupuis, Anne Puel, Fréderic Batteux, Flore Rozenberg, Nico Marr, Qiang Pan-Hammarström, 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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1826-1847.e31
Issue number7
StatePublished - Dec 23 2020


  • IFN-γ
  • Mendelian susceptibility to mycobacterial disease
  • T-bet
  • immunodeficiency
  • inborn errors of immunity
  • innate lymphocyte
  • innate-like adaptive lymphocyte
  • mycobacterium

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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