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Foxp3 expression in induced regulatory T cells is stabilized by C/EBP in inflammatory environments
Author(s) -
Lee Sungkyu,
Park Kyungsoo,
Kim Jieun,
Min Hyungyu,
Seong Rho H
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201845995
Subject(s) - foxp3 , inflammation , microbiology and biotechnology , gene expression , expression (computer science) , regulation of gene expression , biology , chemistry , cancer research , gene , immunology , genetics , immune system , computer science , programming language
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.