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

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 (T reg ) 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 T reg cell conversion. However, it is not known how naive CD 4 + T cells overcome the inhibitory environment in inflamed sites to differentiate into T reg cells. Here, we show that CCAAT /enhancer‐binding protein (C/ EBP ) functions as a safeguard that enhances T reg cell generation by dampening the inhibitory effect of IFN ‐γ and IL ‐4 on Foxp3 expression. We find that C/ EBP β is induced by retinoic acid and binds to the methyl‐ CRE sequence in the Foxp3 TSDR to sustain its expression. C/ EBP β‐transduced iT reg cells show more potent suppressive activity in mouse disease models. We also reveal that C/ EBP β‐transduced human iT reg cells exhibit more enhanced suppressor function. These results establish C/ EBP as a new molecular target for enhancing the formation and stability of T reg cells in inflammatory environments.