The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory Th1 cell fate determination

J Exp Med. 2018 Jul 2;215(7):1813-1821. doi: 10.1084/jem.20170155. Epub 2018 May 17.


Type 1 T helper (Th1) cells play a critical role in host defense against intracellular pathogens and in autoimmune diseases by producing a key inflammatory cytokine interferon (IFN)-γ; some Th1 cells can also be antiinflammatory through producing IL-10. However, the molecular switch for regulating the differentiation of inflammatory and antiinflammatory Th1 cells is still elusive. Here, we show that Bhlhe40-deficient CD4 Th1 cells produced less IFN-γ but substantially more IL-10 than wild-type Th1 cells both in vitro and in vivo. Bhlhe40-mediated IFN-γ production was independent of transcription factor T-bet regulation. Mice with conditional deletion of Bhlhe40 in T cells succumbed to Toxoplasma gondii infection, and blockade of IL-10 signaling during infection rescued these mice from death. Thus, our results demonstrate that transcription factor Bhlhe40 is a molecular switch for determining the fate of inflammatory and antiinflammatory Th1 cells.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Differentiation
  • Cell Lineage*
  • Colitis / immunology
  • Colitis / pathology
  • Disease Susceptibility
  • Homeodomain Proteins / metabolism*
  • Inflammation / immunology*
  • Inflammation / pathology*
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Th1 Cells / immunology*
  • Toxoplasmosis / immunology
  • Toxoplasmosis / pathology


  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlhe40 protein, mouse
  • Homeodomain Proteins
  • Interleukin-10
  • Interferon-gamma