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Cutting Edge: TGF-β-Induced Expression of Foxp3 in T cells Is Mediated through Inactivation of ERK

Xunrong Luo^1,*,,, Qiang Zhang, Victoria Liu, Zhenbiao Xia^*, Kathryn L. Pothoven and Chung Lee^1,,

^* Department of Medicine, Department of Surgery, Department of Urology, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611

The peripheral induction of T regulatory cells can be accomplished by TGF-β through an epigenetic regulation leading to the expression of Foxp3. However, the exact mechanism of such a TGF-β-mediated action remains unclear. In the current study, we found that TGF-β treatment of CD4⁺CD25^– T cells during T cell activation led to a transient inhibition of the phosphorylation of ERK followed by the induction of Foxp3 expression in these cells. Direct treatment with a specific ERK inhibitor, UO126, during CD4⁺CD25^– T cell activation also induced Foxp3 expression and conferred a suppressive function to the induced Foxp3⁺ T cells. Furthermore, treatment of T cells with either TGF-β or UO126 significantly down-regulated the expression of DNMTs, a reaction normally elicited by demethylation agents, such as 5-Aza-2'-deoxycytidine. These results indicate that the epigenetic regulation of TGF-β-induced expression of Foxp3 may be mediated through the inactivation of ERK.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Xunrong Luo, 303 East Chicago Avenue, Tarry Building 11-723, Chicago, IL 60611. E-mail address: xunrongluo@northwestern.edu or Dr. Chung Lee, 303 East Chicago Avenue, Tarry Building 16-733, Chicago, IL 60611. E-mail address: c-lee7{at}northwestern.edu

² Abbreviations used in this paper: Treg, T regulatory cell; 5-Aza, 5-Aza-2'-deoxycytidine; DC, dendritic cell; DNMT, DNA methyltransferase; p-ERK, phosphorylated ERK.