Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells
Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells
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DOI：
10.1016/j.bbrc.2014.06.110
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发表时间：
2014-07-18
影响因子：
3.1
通讯作者：
Oh, Kwon Ik
中科院分区：
文献类型：
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作者：
Nair, Varun Sasidharan;Oh, Kwon Ik
Foxp3 在调节性 T (Treg) 细胞中的稳定表达取决于 Treg 细胞特异性去甲基化区域 (TSDR) 的表观遗传变化（去甲基化）等内在因素和炎症等环境因素。据报道，白介素 2 (IL2) 是向 Foxp3 稳定性发出信号的细胞因子之一，但其潜在机制仍不清楚。在这里，我们发现IL2和foxp3基因座的表观遗传变化通过tet甲基胞嘧啶双加氧酶2（Tet2）紧密相连，共同帮助Treg细胞稳定表达Foxp3。 Foxp3基因座中的TSDR没有去甲基化，并且Foxp3表达在IL2缺陷的Treg细胞中不稳定，重组IL2不能恢复这种情况，但与Tet2的下调相关。 Tet2 被 TCR 信号传导上调，而 IL2 的影响最小。相反，IL2 似乎间接维持了 Tet2 的高水平。此外，Tet2 的过度表达恢复了 IL2 缺陷的 Treg 前体中 TSDR 去甲基化。总的来说，我们的结果表明，Foxp3 稳定性需要 Tet2 的上调，而胸腺 Treg 发育过程中需要 IL2 来维持 Tet2 的高水平。 (C) 2014 Elsevier Inc. 保留所有权利。
Stable expression of Foxp3 in regulatory T (Treg) cells is dependent on both intrinsic factors like epigenetic changes (demethylation) of Treg cell specific demethylation region (TSDR) and environmental cues like inflammations. Interleukin-2 (IL2) was reported to be one of the cytokines that give signals to Foxp3 stability but the underlying mechanism is still elusive. Here we show that IL2 and epigenetic changes in foxp3 locus are closely connected through tet methylcytosine dioxygenase 2 (Tet2) and, together help Treg cells to express Foxp3 stably. TSDR in foxp3 locus was not demethylated and Foxp3 expression was labile in IL2 deficient Treg cells, which was not restored by recombinant IL2, but correlated with the down-regulation of Tet2. Tet2 was up-regulated by TCR signaling and IL2 had a minimal effect. Rather, IL2 seemed to maintain the high level of Tet2 indirectly. Furthermore, over-expression of Tet2 restored TSDR demethylation in IL2 deficient Treg precursors. Collectively, our results suggest that upregulation of Tet2 is required for Foxp3 stability and IL2 is required to maintain the high level of Tet2 during the thymic Treg development. (C) 2014 Elsevier Inc. All rights reserved.