Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation

Nat Commun. 2014 Apr 3;5:3551. doi: 10.1038/ncomms4551.

Abstract

TH1 and TH17 cells mediate neuroinflammation in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Pathogenic TH cells in EAE must produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). TH cell pathogenicity in EAE is also regulated by cell-intrinsic production of the immunosuppressive cytokine interleukin 10 (IL-10). Here we demonstrate that mice deficient for the basic helix-loop-helix (bHLH) transcription factor Bhlhe40 (Bhlhe40(-/-)) are resistant to the induction of EAE. Bhlhe40 is required in vivo in a T cell-intrinsic manner, where it positively regulates the production of GM-CSF and negatively regulates the production of IL-10. In vitro, GM-CSF secretion is selectively abrogated in polarized Bhlhe40(-/-) TH1 and TH17 cells, and these cells show increased production of IL-10. Blockade of IL-10 receptor in Bhlhe40(-/-) mice renders them susceptible to EAE. These findings identify Bhlhe40 as a critical regulator of autoreactive T-cell pathogenicity.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology*
  • Humans
  • Interleukin-10 / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Receptors, Interleukin-10 / genetics
  • Receptors, Interleukin-10 / immunology
  • Th1 Cells / immunology
  • Th17 Cells / immunology

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlhe40 protein, mouse
  • Homeodomain Proteins
  • Receptors, Interleukin-10
  • Interleukin-10
  • Granulocyte-Macrophage Colony-Stimulating Factor

Associated data

  • GEO/GSE49166