@article{237ffaac1a54473ca1c8fc9c2b6196f5,
title = "DNA demethylation fine-tunes IL-2 production during thymic regulatory T cell differentiation",
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.",
keywords = "DNA demethylation, FoxP3, IL-2, Tet enzymes, Treg development",
author = "Athmane Teghanemt and Kara Misel-Wuchter and Jace Heath and Andrew Thurman and Priyanjali Pulipati and Garima Dixit and Ramasatya Geesala and Meyerholz, {David K.} and Thorsten Maretzky and Alejandro Pezzulo and Issuree, {Priya D.}",
note = "Funding Information: We thank members at the Flow Cytometry Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa. The facility is funded through user fees and the generous financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center, and Iowa City Veteran's Administration Medical Center. We are grateful to Dr. Y. Zhang and Dr. I. Aifantis for sharing Tet-mutant mice. We also thank the Comparative Pathology Laboratory, a Pathology Department Research Core that is partially supported by the NIH (HL163556, HL152960, DK124207, and HL091842) and Cystic Fibrosis Foundation. Work in the Issuree laboratory was in part funded by predoctoral fellowships T32AI007511 awarded to KM-W and T32AI007485 awarded to JH. Funding Information: We thank members at the Flow Cytometry Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa. The facility is funded through user fees and the generous financial support of the Carver College of Medicine, Holden Comprehensive Cancer Center, and Iowa City Veteran's Administration Medical Center. We are grateful to Dr. Y. Zhang and Dr. I. Aifantis for sharing Tet‐mutant mice. We also thank the Comparative Pathology Laboratory, a Pathology Department Research Core that is partially supported by the NIH (HL163556, HL152960, DK124207, and HL091842) and Cystic Fibrosis Foundation. Work in the Issuree laboratory was in part funded by predoctoral fellowships T32AI007511 awarded to KM‐W and T32AI007485 awarded to JH. Publisher Copyright: {\textcopyright} 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.",
year = "2023",
month = may,
day = "4",
doi = "10.15252/embr.202255543",
language = "English (US)",
volume = "24",
journal = "EMBO reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "5",
}