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

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere55543
JournalEMBO reports
Volume24
Issue number5
DOIs
StatePublished - May 4 2023
Externally publishedYes

Keywords

  • DNA demethylation
  • FoxP3
  • IL-2
  • Tet enzymes
  • Treg development

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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