Smad2 positively regulates the generation of Th17 cells.
Development of Foxp3(+) regulatory T cells and pro-inflammatory Th17 cells from naive CD4(+) T cells requires transforming growth factor-β (TGF-β) signaling. Although Smad4 and Smad3 have been previously shown to regulate Treg cell induction by TGF-β, they are not required in the development of Th17 cells. Thus, how TGF-β regulates Th17 cell differentiation remains unclear. In this study, we found that TGF-β-induced Foxp3 expression was significantly reduced in the absence of Smad2. More importantly, Smad2 deficiency led to reduced Th17 differentiation in vitro and in vivo. In the experimental autoimmune encephalomyelitis model, Smad2 deficiency in T cells significantly ameliorated disease severity and reduced generation of Th17 cells. Furthermore, we found that Smad2 associated with retinoid acid receptor-related orphan receptor-γt (RORγt) and enhanced RORγt-induced Th17 cell generation. These results demonstrate that Smad2 positively regulates the generation of inflammatory Th17 cells.
Martinez
Gustavo J
GJ
Department of Immunology and Center for Inflammation and Cancer, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Zhang
Zhengmao
Z
Reynolds
Joseph M
JM
Tanaka
Shinya
S
Chung
Yeonseok
Y
Liu
Ting
T
Robertson
Elizabeth
E
Lin
Xia
X
Feng
Xin-Hua
XH
Dong
Chen
C
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004679:Encephalomyelitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D057093:Orphan Nuclear Receptors; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta