Article: DNA demethylation fine-tunes IL-2 production during thymic regulatory T cell differentiation

Authors: Athmane Teghanemt, Kara Misel-Wuchter, Jace Heat, Andrew Thurman, Priyanjali Pulipati, Garima Dixit, Ramasatya Geesala, David K Meyerholz, Thorsten Maretzky, Alejandro Pezzulo, Priya D Issuree

Journal: EMBO Rep. 2023 May 4;24(5):e55543

Abstract:
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- FoxP3lo 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.

Link to journal online:
https://www.embopress.org/doi/full/10.15252/embr.202255543