Induction of Foxp3 demethylation increases regulatory CD4+CD25+ T cells and prevents the occurrence of diabetes in mice
Induction of Foxp3 demethylation increases regulatory CD4+CD25+ T cells and prevents the occurrence of diabetes in mice
复制标题
诱导 Foxp3 去甲基化增加调节性 CD4 CD25 T 细胞并预防小鼠糖尿病的发生
DOI：
10.1007/s00109-009-0530-8
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发表时间：
2009-12-01
影响因子：
4.7
通讯作者：
Zhao, Yong
中科院分区：
文献类型：
--
作者：
Zheng, Qanhui;Xu, Yamei;Zhao, Yong
CD 4（+）CD 25（+）调节性T细胞（Treg）是CD 4（+）T细胞的亚群，调节免疫应答。Foxp 3是Treg细胞发育和功能的关键转录因子。在体外T细胞活化过程中，DNA去甲基化剂5-氮杂-2 '-脱氧胞苷（DAC）可以通过改变Foxp 3基因5'-非翻译区保守元件的甲基化状态，诱导CD 4（+）CD 25（-）Foxp 3（-）细胞中Foxp 3的表达。然而，这种药剂对胸腺和体内Foxp 3（+）Treg细胞发育的影响知之甚少。在本研究中，低剂量DAC短期治疗显著增加了胸腺CD 4（+）CD 8（-）CD 25（+）细胞或CD 4（+）CD 8（-）Foxp 3（+）细胞与CD 4（+）CD 8（-）细胞的比率，以及小鼠胸腺中的CD 4（+）CD 8（-）Foxp 3（+）Treg细胞或CD 4（+）CD 8（-）CD 25（+）Foxp 3（+）Treg细胞的总数。DAC处理主要诱导CD 4（+）CD 8（-）CD 25（+）细胞中Foxp 3的表达和Foxp 3基因第一内含子中CpG岛的显著去甲基化。此外，DAC处理小鼠的CD 4（+）CD 8（-）CD 25（+）胸腺细胞比对照小鼠表现出更强的免疫抑制功能。此外，DAC体内治疗可有效改善环磷酰胺（CY）增强的非肥胖糖尿病小鼠（CY-NOD）的糖尿病临床病程。因此，DAC的体内治疗可以通过Foxp 3去甲基化显著促进天然胸腺CD 4（+）CD 25（+）Foxp 3（+）Treg细胞的发育，暗示DAC在患有自身免疫性疾病的患者中的治疗应用。
CD4(+)CD25(+) regulatory T cells (Treg), a subpopulation of CD4(+) T cells, regulate immune responses. Foxp3 is a key transcription factor for the development and function of Treg cells. During T-cell activation in vitro, a DNA demethylation agent 5-Aza-2'-deoxycytydine (DAC) can induce Foxp3 expression in CD4(+)CD25(-) Foxp3(-) cells via altering methylation status of a conserved element in the 5'-untranslated region of the Foxp3 gene. However, the effects of this agent on the development of Foxp3(+) Treg cells in the thymus and in vivo are poorly understood. In the present study, a short-term treatment with a low dose of DAC significantly increased the ratios of thymic CD4(+)CD8(-) CD25(+) cells or CD4(+)CD8(-) Foxp3(+) cells to CD4(+)CD8(-) cells, and the total numbers of thymic CD4(+)CD8(-)Foxp3(+) Treg cells or CD4(+)CD8(-)CD25(+)Foxp3(+) Treg cells in the thymus in mice. DAC-treatment induced the Foxp3 expression and the significant demethylation of a CpG island in the first intron of the Foxp3 gene in CD4(+)CD8(-)CD25(+) cells predominantly. Furthermore, CD4(+)CD8(-)CD25(+) thymocytes in DAC-treated mice exhibited enhanced immunosuppressive function than those in control mice. In addition, DAC treatment in vivo was effective in improving the clinical course of diabetes in cyclophosphamide (CY)-potentiated non-obese diabetic mice (CY-NOD). Thus, the in vivo treatment with DAC can significantly promote the development of natural thymic CD4(+)CD25(+)Foxp3(+) Treg cells through Foxp3 demethylation, implicating a therapeutic application of DAC in patients suffering from autoimmune diseases.