期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 213, 期 3, 页码 377-397出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151438
关键词
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资金
- National Institutes of Health Research Project [AI44432, CA151535, HL114093]
- Translational Research Program Award from the Leukemia and Lymphoma Society [TRP 6464-15]
- Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research
- Finnish Doctoral Program in Computational Sciences
- Irvington postdoctoral fellowships from the Cancer Research Institute
- National Science Foundation
- Cancer Research Institute
- California Institute for Regenerative Medicine, University of California, San Diego Interdisciplinary Stem Cell Research and Training Grant II [TG2-01154]
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-beta-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.
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