Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity.
Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity.
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蛋白磷酸酶6(PP6)在自身免疫中对调节性T细胞的功能和稳定性至关重要。
DOI：
10.1016/j.gendis.2021.07.005
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发表时间：
2022-03
期刊：
影响因子：
6.8
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Cai W;Zhang J;Zhou H;Li X;Lou F;Sun Y;Xu Z;Bai J;Yin Q;Wang Z;Sun L;Cai X;Tang S;Wu Y;Fan L;Wang H;Wang H;Li Q
调节性T （Treg）细胞构成了一个动态的群体，在自身免疫中是至关重要的。Treg细胞治疗自身免疫性疾病主要集中在增强其抑制活性。然而，最近的研究表明，某些炎症条件诱导Treg细胞不稳定，FoxP3表达降低，并将其转化为致病效应细胞。因此，鉴定对Treg细胞功能和可塑性都至关重要的新靶点对自身免疫治疗方法的发展至关重要。在本研究中，我们发现Treg细胞中的条件Pp6敲除（cKO）导致小鼠自发性自身炎症、免疫细胞激活和CD4+ T细胞中FoxP3水平降低。Treg细胞中Pp6的缺失加重了两种经典的Treg相关自身炎症小鼠模型。机制上，Pp6缺失通过Dnmt1的去磷酸化和Akt在Ser473/Thr308位点的磷酸化，增加了FoxP3位点的CpG基序甲基化，导致FoxP3在Treg细胞中的表达受损。综上所述，我们的研究提出Pp6是FoxP3的关键正调控因子，通过降低FoxP3基因增强子的DNA甲基化和抑制Akt信号传导，从而维持Treg细胞的稳定性和预防自身免疫性疾病。
Regulatory T (Treg) cells constitute a dynamic population that is critical in autoimmunity. Treg cell therapies for autoimmune diseases are mainly focused on enhancing their suppressive activities. However, recent studies demonstrated that certain inflammatory conditions induce Treg cell instability with diminished FoxP3 expression and convert them into pathogenic effector cells. Therefore, the identification of novel targets crucial to both Treg cell function and plasticity is of vital importance to the development of therapeutic approaches in autoimmunity. In this study, we found that conditional Pp6 knockout (cKO) in Treg cells led to spontaneous autoinflammation, immune cell activation, and diminished levels of FoxP3 in CD4+ T cells in mice. Loss of Pp6 in Treg cells exacerbated two classical mouse models of Treg-related autoinflammation. Mechanistically, Pp6 deficiency increased CpG motif methylation of the FoxP3 locus by dephosphorylating Dnmt1 and enhancing Akt phosphorylation at Ser473/Thr308, leading to impaired FoxP3 expression in Treg cells. In summary, our study proposes Pp6 as a critical positive regulator of FoxP3 that acts by decreasing DNA methylation of the FoxP3 gene enhancer and inhibiting Akt signaling, thus maintaining Treg cell stability and preventing autoimmune diseases.
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影响因子：
16.6
作者：
Manzella, Gabriele;Schreck, Leonie D.;Wachtel, Marco
通讯作者：
Wachtel, Marco
影响因子：
100.3
作者：
Huehn, Jochen;Polansky, Julia K.;Hamann, Alf
通讯作者：
Hamann, Alf
影响因子：
3.5
作者：
Sacco F;Perfetto L;Castagnoli L;Cesareni G
通讯作者：
Cesareni G
影响因子：
20.3
作者：
Wang, Liqing;Liu, Yujie;Hancock, Wayne W.
通讯作者：
Hancock, Wayne W.
DOI：
10.1073/pnas.0800928105
发表时间：
2008-06-03
影响因子：
11.1
作者：
Sauer, Stephan;Bruno, Ludovica;Merkenschlager, Matthias
通讯作者：
Merkenschlager, Matthias