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

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

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
2
Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
3
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.

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.

PMID:
24699451
PMCID:
PMC4016562
DOI:
10.1038/ncomms4551
[Indexed for MEDLINE]
Free PMC Article

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