Smad3 Differentially Regulates the Induction of Regulatory and Inflammatory T Cell Differentiation

Anton M. Jetten,Gustavo J. Martinez,Yeonseok Chung,Chen Dong,Xin-Hua Feng,Joseph M. Reynolds,Zhengmao Zhang,Xia Lin

doi:10.1074/jbc.c109.078238

Abstract

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.

Highlights

Transforming growth factor ␤ (TGF-␤) is a crucial cytokine with pleiotropic functions on immune cells
We found that inhibition of TGF-␤ receptor I (TGF-␤RI) activity blocked both iTreg and Th17 differentiation [5]
Smad3 is required for optimal induction of iTreg cells, it appears to negatively regulate Th17 cell differentiation, possibly by direct binding to receptor ␥t (ROR␥t)

Summary

Introduction

Transforming growth factor ␤ (TGF-␤) is a crucial cytokine with pleiotropic functions on immune cells. Induction of Foxp3 expression by TGF-␤ in naive T cells was significantly reduced in the absence of this molecule. Smad3 is required for optimal induction of iTreg cells, it appears to negatively regulate Th17 cell differentiation, possibly by direct binding to ROR␥t.

Results

Conclusion