Abstract
TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine and other oxidized methylcytosines in DNA. Here we examine the role of TET proteins in regulatory T (Treg) cells. Tet2/3fl/flFoxp3Cre mice lacking Tet2 and Tet3 in Treg cells develop inflammatory disease, and Treg cells from these mice show altered expression of Treg signature genes and upregulation of genes involved in cell cycle, DNA damage and cancer. In littermate mice with severe inflammation, both CD4+Foxp3+ and CD4+Foxp3− cells show strong skewing towards Tfh/Th17 phenotypes. Wild-type Treg cells in mixed bone marrow chimeras and in Tet2/3fl/flFoxp3WT/Cre heterozygous female mice are unable to rescue the aberrant properties of Tet2/3fl/flFoxp3Cre Treg cells. Treg cells from Tet2/3fl/flFoxp3Cre mice tend to lose Foxp3 expression, and 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.
Highlights
TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine and other oxidized methylcytosines in DNA
The titer of serum IgG2b isotype was significantly higher in Tet2/3fl/flFoxp3Cre mice than in Wild type (WT) mice, and there was a tendency towards increased titers of serum IgG1, IgG2a, IgG3, and IgM, which correlated with the severity of disease development in the mice
Given that TET proteins catalyze the process of loss of 5mC at CNS1 and CNS2 during Treg development in vivo[12], we examined the DNA modification status at Foxp[3] CNS1 and CNS2 in CD4+CD25+YFP+ peripheral Treg cells isolated from male WT or Tet2/3fl/flFoxp3Cre mice using bisulfite-sequencing (BS-seq) (Supplementary Fig. 6a)
Summary
TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine and other oxidized methylcytosines in DNA. Treg cells from Tet2/3fl/flFoxp3Cre mice tend to lose Foxp[3] expression, and 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 Tet[2] and Tet[3] are guardians of Treg cell stability and immune homeostasis. Tregspecific genetic ablation of many gene products—including cell surface proteins such as neuropilin[1], transcription factors such as NR4A, signaling molecules such as PTEN, and epigenetic regulators such as EZH2—results in instability of Treg Foxp[3] expression and/or loss of suppressive function[7,8,9,10,11]. It is important to understand how DNA methylation is regulated at these elements, and how it in turn controls the stability and function of Treg cells
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