Foxp3 expression in induced regulatory T cells is stabilized by C/EBP in inflammatory environments.
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ABSTRACT: Proper control of immune responses by Foxp3+ regulatory T cells at inflamed sites is crucial for the prevention of immunopathology. TGF-?-induced Foxp3+ regulatory T (Treg) cells are generated in inflammatory environments as well as in steady-state conditions. Inflammatory cytokines such as IFN-? 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-? and IL-4 on Foxp3 expression. We find that C/EBP? is induced by retinoic acid and binds to the methyl-CRE sequence in the Foxp3 TSDR to sustain its expression. C/EBP?-transduced iTreg cells show more potent suppressive activity in mouse disease models. We also reveal that C/EBP?-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.
SUBMITTER: Lee S
PROVIDER: S-EPMC6280649 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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