Regulatory T (T reg) cells are required for the maintenance of immune homeostasis. Both TGF-β signaling and epigenetic modifications are important for Foxp3 induction, but how TGF-β signaling participates in the epigenetic regulation of Foxp3 remains largely unknown. Here we showed that T cell–specific ablation of Uhrf1 resulted in T reg–biased differentiation in TCR-stimulated naive T cells in the absence of TGF-β signaling, and these Foxp3+ T cells had a suppressive function. Adoptive transfer of Uhrf1−/− naive T cells could significantly suppress colitis due to increased iT reg cell generation. Mechanistically, Uhrf1 was induced upon TCR stimulation and participated in the maintenance of DNA methylation patterns of T reg cell–specific genes during cell division, while it was phosphorylated upon TGF-β stimulation and sequestered outside the nucleus, and ultimately underwent proteasome-dependent degradation. Collectively, our study reveals a novel epigenetic mechanism of TGF-β–mediated iT reg cell differentiation by modulating Uhrf1 activity and suggests that Uhrf1 may be a potential therapeutic target in inflammatory diseases for generating stable iT reg cells.
TGF-β signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity
X. Sun and Y. Cui contributed equally to this paper.
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Xiang Sun, Yu Cui, Haiyun Feng, Haifeng Liu, Xiaolong Liu; TGF-β signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity. J Exp Med 2 December 2019; 216 (12): 2819–2837. doi: https://doi.org/10.1084/jem.20190550
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