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 T _H 1 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 T _H 1 ^∗ 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 T _H 1 ^∗ cells unable to compensate for this deficit.
Competing Interests: Declaration of Interests L.H.G. serves on the Board of Directors of GlaxoSmithKline Pharmaceutical Company and the Analog Device Corporation and formerly served on the Boards of Bristol Myers Squibb Pharmaceutical Company and the Waters Corporation. She is also on the Scientific Advisory Boards of Abpro, Kaleido, and Repare biotechnology companies. J.-L.C. serves on the Scientific Advisory Boards of ADMA Biologics Inc., Celgene, and Kymera Therapeutics, Inc. He also consults for Elixiron Immunotherapeutics. Other authors declare no competing interests.
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