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

S Lee, K Park, J Kim, H Min, RH Seong - EMBO reports, 2018 - embopress.org
S Lee, K Park, J Kim, H Min, RH Seong
EMBO reports, 2018embopress.org
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 CD 4+ T cells overcome the inhibitory environment in
inflamed sites to differentiate into Treg cells. Here, we show that CCAAT/enhancer‐binding …
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.
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