T cell receptor-mediated protein geranylgeranylation controls transforming growth factor-beta-induced Foxp3 expression by regulating the induction of Smad6/7 (50.40)

Abstract

Abstract TGF- β plays a critical role as a differentiation factor for the generation of Foxp3+ induced T regulatory cells (iTregs) from naïve T cells. To evaluate the potential role of the mevalonate pathway in the control of iTreg development, we have used the mevalonate pathway inhibitor, Simvastatin. When CD4+Foxp3- T cells were activated with anti-CD3/CD28, the addition of Simvastatin increased the induction of Foxp3+ T cells. A marked synergistic induction of Foxp3 expression was observed when Simvastatin was added to the induction cultures with a suboptimal concentration of TGF-β. The action of Simvastatin was not mediated by enhancement of Smad3 phosphorylation, but was associated with marked inhibition of induction of the Smad 6/7 proteins. The synergistic effect was mediated at the level of mRNA transcription and was associated with increased DNA demethylation of the Foxp3 promoter. The effects of Simvastatin and TGF-βon the induction of Foxp3 expression were reproduced by the addition of an inhibitor of protein geranylgeranylation, but not an inhibitor of protein farnesylation. These studies demonstrate that protein geranylgeranylation represents of one of the key regulatory steps in the generation of iTregs by TGF-β. Pharmacologic manipulation of the mevalonate pathway may represents one mechanism for the induction of iTregs in vivo.