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

Cell. 2020 Dec 23;183(7):1826-1847.e31. doi: 10.1016/j.cell.2020.10.046. Epub 2020 Dec 8.


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.

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

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity*
  • Amino Acid Sequence
  • Base Sequence
  • Cell Lineage
  • Child, Preschool
  • Chromatin / metabolism
  • CpG Islands / genetics
  • DNA Methylation / genetics
  • Dendritic Cells / metabolism
  • Epigenesis, Genetic
  • Female
  • Homozygote
  • Humans
  • INDEL Mutation / genetics
  • Immunity, Innate*
  • Infant
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / metabolism
  • Loss of Function Mutation / genetics
  • Male
  • Mycobacterium / immunology*
  • Mycobacterium Infections / genetics
  • Mycobacterium Infections / immunology
  • Mycobacterium Infections / microbiology
  • Pedigree
  • T-Box Domain Proteins / chemistry
  • T-Box Domain Proteins / deficiency
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • T-Lymphocytes, Helper-Inducer / immunology
  • Transcriptome / genetics


  • Chromatin
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Interferon-gamma