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Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity
Genes & Diseases ( IF 6.9 ) Pub Date : 2021-08-17 , DOI: 10.1016/j.gendis.2021.07.005
Wei Cai 1 , Junxun Zhang 1 , Hong Zhou 1 , Xiangxiao Li 2 , Fangzhou Lou 1 , Yang Sun 1 , Zhenyao Xu 1 , Jing Bai 1 , Qianqian Yin 1 , Zhikai Wang 1 , Libo Sun 1 , Xiaojie Cai 1 , Sibei Tang 1 , Yue Wu 1 , Li Fan 1 , Hong Wang 1 , Honglin Wang 1 , Qun Li 2
Affiliation  

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.



中文翻译:

蛋白磷酸酶 6 (Pp6) 对调节性 T 细胞功能和自身免疫稳定性至关重要

调节性 T (T reg ) 细胞构成了对自身免疫至关重要的动态群体。自身免疫性疾病的T reg细胞疗法主要集中在增强其抑制活性。然而,最近的研究表明,某些炎症状况会导致 T reg细胞不稳定,并降低 FoxP3 的表达,并将它们转化为致病效应细胞。因此,鉴定对 T reg细胞功能和可塑性都至关重要的新靶点对于开发自身免疫治疗方法至关重要。在这项研究中,我们发现T reg中的条件性 Pp6敲除 (cKO)细胞导致自发性自身炎症、免疫细胞激活和小鼠CD4 + T 细胞中 FoxP3 水平降低。T reg细胞中 Pp6 的缺失加剧了 T reg相关自身炎症的两种经典小鼠模型。从机制上讲,Pp6 缺乏通过去磷酸化 Dnmt1 和增强 Ser473/Thr308 处的 Akt 磷酸化来增加FoxP3基因座的CpG 基序甲基化,从而导致 T reg细胞中FoxP3表达受损。总之,我们的研究提出 Pp6 作为 FoxP3 的关键正调节因子,通过降低 FoxP3 基因增强子的 DNA 甲基化和抑制 Akt 信号传导来发挥作用,从而维持 T reg细胞稳定性和预防自身免疫性疾病。

更新日期:2021-08-17
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