DNA demethylation fine‐tunes IL‐2 production during thymic regulatory T cell differentiation

Regulatory T (T reg) cells developing in the thymus are essential to maintain tolerance and prevent fatal autoimmunity in mice and humans. Expression of the T reg lineage‐defining transcription factor FoxP3 is critically dependent upon T cell receptor (TCR) and interleukin‐2 (IL‐2) signaling. Here, we report that ten‐eleven translocation (Tet) enzymes, which are DNA demethylases, are required early during double‐positive (DP) thymic T cell differentiation and prior to the upregulation of FoxP3 in CD4 single‐positive (SP) thymocytes, to promote Treg differentiation. We show that Tet3 selectively controls the development of CD25(−) FoxP3(lo) CD4SP Treg cell precursors in the thymus and is critical for TCR‐dependent IL‐2 production, which drive chromatin remodeling at the FoxP3 locus as well as other Treg‐effector gene loci in an autocrine/paracrine manner. Together, our results demonstrate a novel role for DNA demethylation in regulating the TCR response and promoting Treg cell differentiation. These findings highlight a novel epigenetic pathway to promote the generation of endogenous Treg cells for mitigation of autoimmune responses.