Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity

Wei Cai; Junxun Zhang; Hong Zhou; Xiangxiao Li; Fangzhou Lou; Yang Sun; Zhenyao Xu; Jing Bai; Qianqian Yin; Zhikai Wang; Libo Sun; Xiaojie Cai; Sibei Tang; Yue Wu; Li Fan; Hong Wang; Honglin Wang; Qun Li

doi:10.1016/j.gendis.2021.07.005

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Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity

更新时间：2022-06-24

- Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity
- Genes & Diseases Vol. 9, Issue 2, (2022)
- 作者机构：
  
  1. Department of Immunology and Microbiology, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institute of Translational Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine (SJTU-SM),Shanghai,PR China,200025
  2. The Department of Cardiovascular Medicine, State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Institute of Hypertension, Shanghai Jiao Tong University School of Medicine,Shanghai,PR China,200025
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2021.07.005
  CLC：
- Published：2022，
  
  Published Online：1 March 2022，
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Wei Cai, Junxun Zhang, Hong Zhou, et al. Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity. [J]. Genes & Diseases 9(2).(2022)
DOI：

Wei Cai, Junxun Zhang, Hong Zhou, et al. Protein phosphatase 6 (Pp6) is crucial for regulatory T cell function and stability in autoimmunity. [J]. Genes & Diseases 9(2).(2022) DOI： 10.1016/j.gendis.2021.07.005.

摘要

Abstract

Regulatory T (T

reg

) cells constitute a dynamic population that is critical in autoimmunity. T

reg

cell therapies for autoimmune diseases are mainly focused on enhancing their suppressive activities. However

recent studies demonstrated that certain inflammatory conditions induce T

reg

cell instability with diminished FoxP3 expression and convert them into pathogenic effector cells. Therefore

the identification of novel targets crucial to both T

reg

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 T

reg

cells led to spontaneous autoinflammation

immune cell activation

and diminished levels of FoxP3 in CD4

T cells in mice. Loss of Pp6 in T

reg

cells exacerbated two classical mouse models of T

reg

-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 T

reg

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 T

reg

cell stability and preventing autoimmune diseases.

关键词

Keywords

AktDNA methyltransferase 1 (Dnmt1)Foxp3Protein phosphatase 6 (Pp6)Regulatory T (Treg) cellsStability

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