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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.

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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.