Whole-genome analysis of TET dioxygenase function in regulatory T cells.
Whole-genome analysis of TET dioxygenase function in regulatory T cells.
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DOI：
10.15252/embr.202152716
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发表时间：
2021-08-04
期刊：
影响因子：
7.7
通讯作者：
Rao A
中科院分区：
文献类型：
--
作者：
Yue X;Samaniego-Castruita D;González-Avalos E;Li X;Barwick BG;Rao A
泰特甲基胞嘧啶双加氧酶对于调节性T细胞（Treg细胞）的稳定性和功能至关重要，调节性T细胞维持免疫稳态和自身耐受性并表达谱系决定转录因子Foxp3。在这里，我们使用全基因组分析来表明Treg细胞的转录程序和表观遗传特征（DNA修饰，染色质可及性）在不存在Tet2和Tet3的情况下减弱。相反，在体外TGF β诱导的iTreg细胞分化过程中添加泰特激活剂维生素C可增强Treg特征基因的表达，并改变表观遗传格局，使其更类似于体内产生的Treg细胞。维生素C通过增加IL2R α表达、STAT5磷酸化和STAT5结合来增强iTreg细胞中的IL-2反应性，模拟体内产生的Treg细胞的IL-2/STAT5依赖性。综上所述，泰特蛋白在维持Treg分子特征和促进其对IL-2的依赖性方面起着至关重要的作用。内源性Treg发育期间的泰特活性和iTreg分化期间维生素C对泰特活性的增强是维持Treg细胞的转录和表观遗传特征所必需的。对野生型和泰特缺陷型Treg细胞以及用泰特激活剂维生素C处理的iTreg细胞的基因组分析表明，泰特蛋白对于维持Treg特征和IL-2/STAT 5信号传导至关重要。
TET methylcytosine dioxygenases are essential for the stability and function of regulatory T cells (Treg cells), which maintain immune homeostasis and self‐tolerance and express the lineage‐determining transcription factor Foxp3. Here, we use whole‐genome analyses to show that the transcriptional program and epigenetic features (DNA modification, chromatin accessibility) of Treg cells are attenuated in the absence of Tet2 and Tet3. Conversely, the addition of the TET activator vitamin C during TGFβ‐induced iTreg cell differentiation in vitro potentiates the expression of Treg signature genes and alters the epigenetic landscape to better resemble that of Treg cells generated in vivo. Vitamin C enhances IL‐2 responsiveness in iTreg cells by increasing IL2Rα expression, STAT5 phosphorylation, and STAT5 binding, mimicking the IL‐2/STAT5 dependence of Treg cells generated in vivo. In summary, TET proteins play essential roles in maintaining Treg molecular features and promoting their dependence on IL‐2. TET activity during endogenous Treg development and potentiation of TET activity by vitamin C during iTreg differentiation are necessary to maintain the transcriptional and epigenetic features of Treg cells. Genomic analyses of wildtype and TET‐deficient Treg cells, and iTreg cells treated with the TET activator Vitamin C, show that TET proteins are essential for the maintenance of Treg signatures and IL‐2/STAT5 signaling.