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 CD4⁺ 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/EBPβ is induced by retinoic acid and binds to the methyl-CRE sequence in the Foxp3 TSDR to sustain its expression. C/EBPβ-transduced iT_reg cells show more potent suppressive activity in mouse disease models. We also reveal that C/EBPβ-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.