Publication Date:
2018
Description:
Naive CD4+ T cells need to overcome the inhibitory environment at inflamed sites to differentiate into Tregs. C/EBP enhances Treg generation by dampening the inhibitory effect of IFN‐γ and IL‐4 on Foxp3 expression.
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.
Print ISSN:
1469-221X
Electronic ISSN:
1469-3178
Topics:
Biology
,
Medicine
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