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

Chih-Chung Lin, Tara R. Bradstreet, Elizabeth A. Schwarzkopf, Julia Sim, Javier A. Carrero, Chun Chou, Lindsey E. Cook, Takeshi Egawa, Reshma Taneja, Theresa L. Murphy, John H. Russell and Brian T. Edelson ()
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Chih-Chung Lin: Washington University School of Medicine
Tara R. Bradstreet: Washington University School of Medicine
Elizabeth A. Schwarzkopf: Washington University School of Medicine
Julia Sim: Washington University School of Medicine
Javier A. Carrero: Washington University School of Medicine
Chun Chou: Washington University School of Medicine
Lindsey E. Cook: Washington University School of Medicine
Takeshi Egawa: Washington University School of Medicine
Reshma Taneja: Yong Loo Lin School of Medicine, National University of Singapore
Theresa L. Murphy: Washington University School of Medicine
John H. Russell: Washington University School of Medicine
Brian T. Edelson: Washington University School of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4551

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