Foxp3 expression in induced regulatory T cells is stabilized by C/EBP in inflammatory environments

Abstract

Proper control of immune responses by Foxp3+ regulatory T cells at inflamed sites is crucial for the prevention of immunopathology. TGF-β-induced Foxp3+ regulatory T (Treg) cells are generated in inflammatory environments as well as in steady-state conditions. Inflammatory cytokines such as IFN-γ and IL-4 have an antagonistic effect on Treg cell conversion. However, it is not known how naive CD4+ T cells overcome the inhibitory environment in inflamed sites to differentiate into Treg cells. Here, we show that CCAAT/enhancer-binding protein (C/EBP) functions as a safeguard that enhances Treg cell generation by dampening the inhibitory effect of IFN-γ and IL-4 on Foxp3 expression. We find that C/EBPβ is induced by retinoic acid and binds to the methyl-CRE sequence in the Foxp3 TSDR to sustain its expression. C/EBPβ-transduced iTreg cells show more potent suppressive activity in mouse disease models. We also reveal that C/EBPβ-transduced human iTreg cells exhibit more enhanced suppressor function. These results establish C/EBP as a new molecular target for enhancing the formation and stability of Treg cells in inflammatory environments.