Dataset Information

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

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 (T_reg) 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 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-? 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 iT_reg cells show more potent suppressive activity in mouse disease models. We also reveal that C/EBP?-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.

SUBMITTER: Lee S

PROVIDER: S-EPMC6280649 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lee Sungkyu S Park Kyungsoo K Kim Jieun J Min Hyungyu H Seong Rho H RH

EMBO reports 20181022 12

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 i ...[more]

PMID: 30348891

Similar Datasets

Project description:Foxp3 reporter mice including DEREG (DEpletion of REGulatory T cells) mice have greatly helped in exploring the biology of Foxp3(+) Tregs. DEREG mice express a DTR-eGFP fusion protein under the control of a bacterial artificial chromosome (BAC)-encoded Foxp3 promoter, allowing the viable isolation and inducible depletion of Foxp3(+) Tregs. Adaptive Tregs differentiated in vitro to express Foxp3 (iTregs) are gaining high interest as potential therapeutics for inflammatory conditions such as autoimmunity, allergy and transplant rejection. However, selective isolation of Foxp3(+) iTregs with a stable phenotype still remains to be a problem, especially in the human setting. While screening for culture conditions to generate stable CD4(+)Foxp3(+) iTregs from DEREG mice, with maximum suppressive activity, we observed an unexpected dichotomy of eGFP and Foxp3 expression which is not seen in ex vivo isolated cells from DEREG mice. Further characterization of eGFP(+)Foxp3(-) cells revealed relatively lower CD25 expression and a lack of suppressive activity in vitro. Similarly, eGFP(-) cells isolated from the same cultures were not suppressive despite of a broad CD25 expression reflecting mere T cell activation. In contrast, eGFP(+)Foxp3(+) iTregs exhibited potent suppressive activity comparable to that of natural eGFP(+)Foxp3(+) Tregs, emphasizing the importance of isolating Foxp3 expressing iTregs. Interestingly, the use of plate-bound anti-CD3 and anti-CD28 or Flt3L-driven BMDC resulted in considerable resolution of the observed dichotomy. In summary, we defined culture conditions for efficient generation of eGFP(+)Foxp3(+) iTregs by use of DEREG mice. Isolation of functional Foxp3(+) iTregs using DEREG mice can also be achieved under sub-optimal conditions based on the magnitude of surface CD25 expression, in synergy with transgene encoded eGFP. Besides, the reported phenomenon may be of general interest for exploring Foxp3 gene regulation, given that Foxp3 and eGFP expression are driven from distinct Foxp3 loci and because this dichotomy preferentially occurs only under defined in vitro conditions.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets