TET2 and TET3 regulate stability and function of regulatory T cells.

Abstract

Abstract Regulatory T cells (Tregs) play a pivotal role in regulating immune response and maintaining immunological tolerance, and are characterized by the expression of Foxp3. Thymus-derived Tregs have been shown to be relatively stable compared with iTregs generated from naive T cells with TGFβ in vitro. Treg stability is maintained by the epigenetic modification, such as DNA demethylation of Treg-specific demethylation regions (TSDRs) during Treg development in the thymus. In fact, the TSDRs of iTreg are hypermethylated. Although DNA demethylase, ten-eleven translocation (TET) family proteins have been proposed to be involved in the DNA demethylation of TSDRs, actual contribution of TET family proteins in Treg stability and function remains to be elucidated. To investigate the role of TET proteins in Tregs, we generated Treg-specific Tet-deficient (Foxp3YFPCre+Tet2f/fTet3f/f; FDKO) mice. FDKO mice died at an average of 20 weeks of age with splenomegaly and lymph adenopathy accompanied by uncontrolled activation of T cells and B cells. These FDKO mice developed inflammation in the gut, and both Foxp3+ and Foxp3− T cells were expanded and produced high levels of IL-17 especially in gut mucosa and mesenteric lymph nodes. Transfer experiment of FDKO Tregs into lymphopenic mice revealed that Foxp3 expression in FDKO Tregs was unstable and Treg cells which have lost their Foxp3 expression were accumulated. TSDRs of FDKO Tregs were hyper-, but not completely, methylated compared with WT Tregs, indicating that there are TET2/3 dependent and independent mechanisms for TSDR demethylation. These data indicate that TET2 and TET3 are redundantly involved in TSDR demethylation and are important for the stability and homeostasis of Tregs.