Control of Foxp3 stability through modulation of TET activity.
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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.
author list (cited authors)
Yue, X., Trifari, S., Äijö, T., Tsagaratou, A., Pastor, W. A., Zepeda-Martínez, J. A., ... Rao, A.
complete list of authors
Yue, Xiaojing||Trifari, Sara||Äijö, Tarmo||Tsagaratou, Ageliki||Pastor, William A||Zepeda-Martínez, Jorge A||Lio, Chan-Wang J||Li, Xiang||Huang, Yun||Vijayanand, Pandurangan||Lähdesmäki, Harri||Rao, Anjana