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J Exp Med. 2016 Mar 7;213(3):377-97. doi: 10.1084/jem.20151438. Epub 2016 Feb 22.

Control of Foxp3 stability through modulation of TET activity.

Author information

1
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
2
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 Department of Computer Science, Aalto University School of Science, 00076 Aalto, Finland.
3
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037.
4
Department of Computer Science, Aalto University School of Science, 00076 Aalto, Finland.
5
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037 Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037 Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 arao@liai.org.

Abstract

Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4(+) T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell-specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β-induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy.

PMID:
26903244
PMCID:
PMC4813667
DOI:
10.1084/jem.20151438
[Indexed for MEDLINE]
Free PMC Article

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