TET enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines, mediating DNA demethylation and serving as new epigenetic marks. Here we examine the role of TET proteins in Foxp3+ regulatory T (Treg) cells, a distinct lineage of CD4+ T cells that prevent autoimmunity and maintain immune homeostasis. We report that Tet2/3fl/flFoxp3Cre mice that lack Tet2 and Tet3 specifically in Treg cells develop splenomegaly, leukocyte infiltration into tissues

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... nd inflammatory disease. Treg cells from these mice showed altered expression of Treg signature genes, with upregulation of genes involved in cell cycle regulation, DNA damage repair and cancer. In littermate mice with more severe inflammation, both CD4+ Foxp3+ and CD4+ Foxp3- cells showed strong skewing towards Tfh and/or Th17 phenotypes. Notably, the presence of wild type Treg cells in mixed bone marrow chimeras and Tet2/3fl/flFoxp3WT/Cre heterozygous female mice did not suppress the aberrant phenotype and function of Tet2/3fl/flFoxp3Cre Treg cells. Fate-mapping experiments indicated that Treg cells from Tet2/3fl/flFoxp3Cre mice were more prone to lose Foxp3 expression; moreover, transfer of total CD4+ T cells isolated from Tet2/3fl/flFoxp3Cre mice could elicit inflammatory disease in fully immunocompetent mice. Together, these data indicate that Tet2 and Tet3 are guardians of Treg cell stability and immune homeostasis in mice.