| First Author | Sun X | Year | 2019 |
| Journal | J Exp Med | Volume | 216 |
| Issue | 12 | Pages | 2819-2837 |
| PubMed ID | 31515281 | Mgi Jnum | J:285232 |
| Mgi Id | MGI:6392664 | Doi | 10.1084/jem.20190550 |
| Citation | Sun X, et al. (2019) TGF-beta signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity. J Exp Med 216(12):2819-2837 |
| abstractText | Regulatory T (T reg) cells are required for the maintenance of immune homeostasis. Both TGF-beta signaling and epigenetic modifications are important for Foxp3 induction, but how TGF-beta 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-beta 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-beta stimulation and sequestered outside the nucleus, and ultimately underwent proteasome-dependent degradation. Collectively, our study reveals a novel epigenetic mechanism of TGF-beta-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. |
