Activin A Promotes the TGF-β-Induced Conversion of CD4+CD25- T Cells into Foxp3+ Induced Regulatory T Cells

TGF-beta induces the conversion of CD4(+)CD25(-) T cells into CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg). Activin A is a pleiotropic TGF-beta family member and is expressed in response to inflammatory signals. In this study, we report on the effects of activin A on the conversion of CD4(+)CD25(-) T cells into Foxp3-expressing induced Treg (iTreg). Activin A was able to promote the conversion of CD4(+)CD25(-) T cells into iTreg in a dose-dependent manner in vitro. Activin A together with TGF-beta 1 had synergistic effects on the rate of iTreg conversion in vitro. Intact TGF-beta 1 signaling seemed to be essential for the effects of activin A on iTreg generation because cells overexpressing a dominant negative TGF-beta type II receptor could not be converted by activin A in vitro. In vivo, the frequency of peripheral, but not central, Treg was increased in transgenic mice with elevated activin A serum levels and the in vivo conversion rate of CD4(+)CD25(-) T cells into Foxp3-expressing iTreg was increased as compared with wild type mice. These data suggest a role for activin A as a promoter of the TGF-beta dependent conversion of CD4(+)CD25(-) T cells into iTreg in vitro and in vivo. Therefore, besides promoting inflammation, activin A may contribute to the regulation of inflammation via the expansion of peripheral Treg. The Journal of Immunology, 2009, 182: 4633-4640.