Smad3 differentially regulates the induction of regulatory and inflammatory T cell differentiation.
Transforming growth factor beta (TGF-beta) is a crucial cytokine with pleiotropic functions on immune cells. In CD4(+) T cells, TGF-beta is required for induction of both regulatory T and Th17 cells. However, the molecular mechanism underlying this differential T cell fate decision remains unclear. In this study, we have evaluated the role of Smad3 in the development of Th17 and regulatory T cells. Smad3 was found to be dispensable for natural regulatory T cell function. However, induction of Foxp3 expression by TGF-beta in naive T cells was significantly reduced in the absence of this molecule. On the contrary, Smad3 deficiency led to enhanced Th17 differentiation in vitro and in vivo. Moreover, Smad3 was found to interact with retinoid acid receptor-related orphan receptor gammat (RORgammat) and decrease its transcriptional activity. These results demonstrate that Smad3 is differentially involved in the reciprocal regulatory and inflammatory T cell generation.
Martinez
Gustavo J
GJ
Department of Immunology, M. D. Anderson Cancer Center, Houston, Texas 77054, USA.
Zhang
Zhengmao
Z
Chung
Yeonseok
Y
Reynolds
Joseph M
JM
Lin
Xia
X
Jetten
Anton M
AM
Feng
Xin-Hua
XH
Dong
Chen
C
D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539901:Rorc protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta