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

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

Genes Dis. 2021 Aug 17;9(2):562-575. doi: 10.1016/j.gendis.2021.07.005. eCollection 2022 Mar.

Authors

Wei Cai¹, Junxun Zhang¹, Hong Zhou¹, Xiangxiao Li², Fangzhou Lou¹, Yang Sun¹, Zhenyao Xu¹, Jing Bai¹, Qianqian Yin¹, Zhikai Wang¹, Libo Sun¹, Xiaojie Cai¹, Sibei Tang¹, Yue Wu¹, Li Fan¹, Hong Wang¹, Honglin Wang¹, Qun Li²

Affiliations

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 200025, PR China.
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 200025, PR China.

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.

Keywords: Akt; CTV, CellTrace Violet; DNA methyltransferase 1 (Dnmt1); EAE, experimental allergic encephalomyelitis; FoxP3; FoxP3, Forkhead box protein P3; Protein phosphatase 6 (Pp6); Rag1, recombination-activating protein 1; Regulatory T (Treg) cells; Stability; TCR, T cell receptor; TSDR, Treg-specific demethylated region; WT, wild type.