Department of Pathology and Infectious Disease Medical Research Center, Hallym University College of Medicine, Chuncheon, Republic of Korea.
Department of Pathology and Infectious Disease Medical Research Center, Hallym University College of Medicine, Chuncheon, Republic of Korea.
Biochem Biophys Res Commun. 2014 Jul 18;450(1):918-24. doi: 10.1016/j.bbrc.2014.06.110. Epub 2014 Jun 28.
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 up-regulation of Tet2 is required for Foxp3 stability and IL2 is required to maintain the high level of Tet2 during the thymic Treg development.
Foxp3 在调节性 T（Treg）细胞中的稳定表达既依赖于内在因素，如 Treg 细胞特异性去甲基化区域（TSDR）的表观遗传改变（去甲基化），也依赖于环境线索，如炎症。白细胞介素 2（IL2）被报道是给 Foxp3 稳定性信号的细胞因子之一，但潜在的机制仍不清楚。在这里，我们表明，IL2 和 Foxp3 基因座中的表观遗传变化通过四氢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，Foxp3 表达不稳定，在缺乏 IL2 的 Treg 细胞中，这不能通过重组 IL2 恢复，但与 Tet2 的下调相关。Tet2 被 TCR 信号上调，IL2 的作用很小。相反，IL2 似乎间接地维持 Tet2 的高水平。此外，Tet2 的过表达恢复了缺乏 IL2 的 Treg 前体中的 TSDR 去甲基化。总之，我们的结果表明，Tet2 的上调对于 Foxp3 的稳定性是必需的，而 IL2 在胸腺 Treg 发育过程中维持 Tet2 的高水平是必需的。
