Protein phosphatase 2A propels follicular T helper cell development in lupus

Yu Jiang, Institute of Immunology, and Department of Rheumatology in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
Xuexiao Jin, Institute of Immunology, and Department of Rheumatology in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
Zhexu Chi, International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China; Department of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
Yadan Bai, Institute of Immunology, and Department of Rheumatology in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
Kalpana Manthiram, Cell Signaling and Immunity Section, Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
Pamela Mudd, Division of Pediatric Otolaryngology, Children's National Hospital, Washington, DC, USA; Division of Otolaryngology, Department of Surgery, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Kaixiang Zhu, Institute of Immunology, and Department of Rheumatology in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China; Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, 200127, China.
Lie Wang, Department of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
Pamela L. Schwartzberg, Cell Signaling and Immunity Section, Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA.
Yongmei Han, Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, PR China.
Xiang Gao, Key Laboratory of Model Animals for Disease Study of the Ministry of Education, Model Animal Research Center, Nanjing University, Nanjing, 210061, PR China.
Linrong Lu, Institute of Immunology, and Department of Rheumatology in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China; Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, 200127, China. Electronic address: lu_linrong@zju.edu.cn.
Qin Xu, Institute of Immunology, and Department of Rheumatology in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China; Cell Signaling and Immunity Section, Laboratory of Immune System Biology (LISB), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA. Electronic address: qin.xu@nih.gov.

Document Type

Journal Article

Publication Date

4-1-2023

Journal

Journal of autoimmunity

Volume

136

DOI

10.1016/j.jaut.2023.103028

Keywords

PP2A; SLE; Tfh; mTOR

Abstract

Follicular helper T (Tfh) cells are important for generating humoral immune responses by helping B cells form germinal centers (GCs) and the production of high-affinity antibodies. However, aberrant Tfh cell expansion also contributes to the generation of self-reactive autoantibodies and promotes autoantibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Protein phosphatase 2A catalytic subunit alpha isoform (PP2A Cα) expression levels are elevated in peripheral T cells of SLE patients and positively correlate with autoantibody titers and disease activity. Here, we demonstrate a critical role of PP2A in Tfh differentiation by using T cell restricted PP2A Cα deficient mice. We observed impaired Tfh differentiation and GC response in two different classical Tfh induction models. Mechanistic studies revealed that downregulation of protein translation of the Tfh lineage transcription factor BCL6 in PP2A deficient T cells. Importantly, we found that PP2A deficiency by either gene knockout or chemical inhibition alleviated lupus severity in mice. Lastly, we confirmed a positive correlation between PP2A Cα and BCL6 protein levels in human CD4 T cells from patients with SLE. In summary, our study revealed a critical role of PP2A in regulating Tfh cells and suggests it is a potential therapeutic target for lupus.

Department

Surgery

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