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.

调节性T（T reg）细胞是维持免疫稳态所必需的。TGF-β信号传导和表观遗传修饰均对Foxp3的诱导很重要，但是TGF-β信号传导如何参与Foxp3的表观遗传调控仍然是未知的。在这里，我们显示了在没有TGF-β信号传导的情况下，TCR刺激的原始T细胞中Uhrf1的T细胞特异性消融导致T reg-biased分化，并且这些Foxp3 ⁺ T细胞具有抑制功能。Uhrf1的过继转移^-/-由于增加的iT reg细胞生成，幼稚T细胞可以显着抑制结肠炎。从机制上讲，Uhrf1在TCR刺激后被诱导并参与细胞分裂过程中T reg细胞特异性基因的DNA甲基化模式的维持，而Uhrf1在TGF-β刺激下被磷酸化并被隔离在核外，最终经历了蛋白酶体依赖性降解。我们的研究共同揭示了通过调节Uhrf1活性，TGF-β介导的iT reg细胞分化的新表观遗传机制，并暗示Uhrf1可能是炎性疾病中产生稳定iT reg细胞的潜在治疗靶标。