Genes and Diseases (Mar 2022)
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
Affiliations
- Wei Cai
- 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
- Junxun Zhang
- 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
- Hong Zhou
- 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
- Xiangxiao Li
- 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
- Fangzhou Lou
- 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
- Yang Sun
- 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
- Zhenyao Xu
- 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
- Jing Bai
- 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
- Qianqian Yin
- 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
- Zhikai Wang
- 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
- Libo Sun
- 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
- Xiaojie Cai
- 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
- Sibei Tang
- 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
- Yue Wu
- 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
- Li Fan
- 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
- Hong Wang
- 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
- Honglin Wang
- 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; Corresponding author. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine (SJTU-SM), 280 Chongqing South Road, Shanghai 200025, PR China. Fax: +86 21 64660996.
- Qun Li
- 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; Corresponding author. The Department of Cardiovascular Medicine, Shanghai Key Laboratory of Hypertension Ruijin Hospital, Shanghai Institute of Hypertension Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, PR China.
- Journal volume & issue
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Vol. 9,
no. 2
pp. 562 – 575
Abstract
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.
