Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation.
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.
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Chih-Chung
CC
Lin
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Tara R
TR
Bradstreet
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Elizabeth A
EA
Schwarzkopf
Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Julia
J
Sim
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Javier A
JA
Carrero
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Chun
C
Chou
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Lindsey E
LE
Cook
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Takeshi
T
Egawa
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
Reshma
R
Taneja
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Theresa L
TL
Murphy
Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
John H
JH
Russell
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Brian T
BT
Edelson
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology*; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
D051792:Basic Helix-Loop-Helix Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018398:Homeodomain Proteins; D016753:Interleukin-10; D053701:Receptors, Interleukin-10; C491539:Bhlhe40 protein, mouse