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
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
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.
J Exp Med. 2016 Mar 7;213(3):377-97. doi: 10.1084/jem.20151438. Epub 2016 Feb 22.
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.
十一易位（TET）酶将5-甲基胞嘧啶（5mC）氧化为5-羟甲基胞嘧啶及其他氧化甲基胞嘧啶，这些是DNA去甲基化过程中的中间体。在本研究中，我们探究了TET蛋白在调控Foxp3中的作用，Foxp3是调节性T细胞（Treg细胞）发育和功能所必需的转录因子，Treg细胞是一类独特的CD4(+) T细胞谱系，可预防自身免疫并维持免疫稳态。我们发现，在胸腺中Treg细胞发育过程中，TET蛋白介导了Treg细胞特异性低甲基化区域（包括CNS1和CNS2，即Foxp3基因座中的内含子顺式调节元件）中5mC的丢失。与CNS2缺陷的Treg细胞类似，来自Tet2/Tet3双缺陷小鼠的Treg细胞中Foxp3表达的稳定性明显受损。维生素C可增强TET活性，并通过Tet2/Tet3发挥作用，以增加转化生长因子-β诱导的Treg细胞中Foxp3表达的稳定性。我们的数据表明用维生素C等小分子激活剂靶向TET酶可能会提高诱导性Treg细胞的功效。
