DNA demethylation fine-tunes IL-2 production during thymic development and promotes Regulatory T cell differentiation

Abstract Regulatory T (T reg) cells developing in the thymus are essential to maintain tolerance and prevent fatal autoimmunity mice humans. Expression of reg lineage-defining transcription factor FoxP3, is critically dependent upon cell receptor (TCR) interleukin-2 (IL-2) signaling. Here, we report that ten-eleven translocation (Tet) enzymes, which DNA demethylases, required early during double positive (DP) thymic differentiation prior upregulation FoxP3 CD4 single-positive (SP) thymocytes, promote Treg differentiation. We show Tet enzymes selectively control development CD25 −FoxP3 loCD4SPTreg precursors critical for optimal TCR-dependent IL-2 production, drive chromatin remodeling at locus as well other Treg-effector gene loci an autocrine/paracrine manner. Together, our results demonstrate a novel role demethylation regulating TCR response promoting These findings highlight epigenetic pathway generation endogenous mitigation autoimmune responses.