TGF-β signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity

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.