Control of Foxp3 stability through modulation of TET activity.
Control of Foxp3 stability through modulation of TET activity.
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DOI：
10.1084/jem.20151438
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发表时间：
2016-03-07
期刊：
影响因子：
--
通讯作者：
Rao A
中科院分区：
文献类型：
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作者：
Yue X;Trifari S;Äijö T;Tsagaratou A;Pastor WA;Zepeda-Martínez JA;Lio CW;Li X;Huang Y;Vijayanand P;Lähdesmäki H;Rao A
TET2和TET3冗余地调节Foxp3的稳定性，它们的活性可以受到维生素C的调节。Tet-11易位(Tet)酶将5-甲基胞嘧啶(5mC)氧化为5-羟甲基胞嘧啶和其他氧化的甲基胞嘧啶，它们是DNA去甲基化的中间产物。在这项研究中，我们研究了Tet蛋白在调节Foxp3中的作用，Foxp3是调节性T细胞(T reg细胞)发育和功能所必需的转录因子，T reg细胞是一种独特的CD4+T细胞谱系，可以防止自身免疫并维持免疫动态平衡。我们发现，在胸腺T-reg细胞发育过程中，Tet蛋白介导了T-reg细胞特异性低甲基化区域5mC的丢失，包括Foxp3基因内含子顺式调控元件CNS1和CNS2。与CNS2缺陷的T reg细胞相似，在TET2/Tet3双缺陷小鼠的T reg细胞中，Foxp3表达的稳定性明显受损。维生素C增强Tet活性，并通过Tet2/Tet3增加转化生长因子-β诱导的T-reg细胞Foxp3表达的稳定性。我们的数据表明，靶向Tet酶与小分子激活剂，如维生素C，可能会增加诱导的T细胞效率。
TET2 and TET3 redundantly regulate Foxp3 stability, and their activity can be modulated by vitamin C. 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.