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

doi:10.15252/embr.202255543

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

Journal article

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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, …

EMBO reports, Vol.24(5), pp.e55543-e55543

03/07/2023

DOI: 10.15252/embr.202255543

PMCID: PMC10157375

PMID: 36880575

Appears in UI Libraries Support Open Access

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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 FoxP3 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.

Tet enzymes

DNA demethylation

IL-2

Treg development

FoxP3

UIOWA OA Agreement

Details

Title: Subtitle: DNA demethylation fine-tunes IL-2 production during thymic regulatory T cell differentiation
Creators: Athmane Teghanemt - University of Iowa
Kara Misel-Wuchter - Roy J. and Lucille A. Carver College of Medicine
Jace Heath - Roy J. and Lucille A. Carver College of Medicine
Andrew Thurman - University of Iowa
Priyanjali Pulipati - University of Iowa
Garima Dixit - University of Iowa
Ramasatya Geesala - Roy J. and Lucille A. Carver College of Medicine
David K Meyerholz - University of Iowa
Thorsten Maretzky - Roy J. and Lucille A. Carver College of Medicine
Alejandro Pezzulo - Roy J. and Lucille A. Carver College of Medicine
Priya D Issuree - Roy J. and Lucille A. Carver College of Medicine
Resource Type: Journal article
Publication Details: EMBO reports, Vol.24(5), pp.e55543-e55543
DOI: 10.15252/embr.202255543
PMID: 36880575
PMCID: PMC10157375
NLM abbreviation: EMBO Rep
eISSN: 1469-3178
Publisher: Wiley
Grant note: HL152960 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) T32 AI007511 / NIAID NIH HHS T32AI007485 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) DK124207 / HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) HL091842 / UI | Holden Comprehensive Cancer Center, University of Iowa (HCCC) HL163556 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
Language: English
Date published: 03/07/2023
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Infectious Diseases; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Biology; Internal Medicine
Record Identifier: 9984375450902771

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