单位：[1]Division of Rheumatology, Department of Medicine, Mayo Clinic Rochester, MN, USA.[2]Department of Rheumatology, Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China.临床科室风湿内科风湿内科首都医科大学附属北京友谊医院[3]Department of Dermatology, the Second Hospital of Harbin Medical University, Harbin Medical University, Harbin, P. R. China.[4]Division of Laboratory Medicine and Pathology, Mayo Clinic Rochester, MN, USA.[5]Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA.[6]Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA.[7]Department of Immunology, Mayo Clinic Rochester, MN, USA.
The development of many systemic autoimmune diseases, including systemic lupus erythematosus, is associated with overactivation of the type I interferon (IFN) pathway, lymphopenia, and increased follicular helper T (Tfh) cell differentiation. However, the cellular and molecular mechanisms underlying these immunological perturbations remain incompletely understood. Here we show that the mechanistic target of rapamycin complex 2 (mTORC2) promotes Tfh differentiation and disrupts Treg homeostasis. Inactivation of mTORC2 in total T cells, but not in Tregs, greatly ameliorated the immunopathology in a systemic autoimmunity mouse model. This was associated with reduced Tfh differentiation, B cell activation, and reduced T cell glucose metabolism. Finally, we show that type I IFN can synergize with TCR ligation to activate mTORC2 in T cells, which partially contributes to T cell lymphopenia. These data indicate that mTORC2 may act as downstream of type I IFN, TCR, and costimulatory receptor ICOS, to promote glucose metabolism, Tfh differentiation, and T cell lymphopenia, but not to suppress Treg function in systemic autoimmunity. Our results suggest that mTORC2 might be a rational target for systemic autoimmunity treatment. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.
基金：
Center for Biomedical Discovery at Mayo
Clinic; National Institute of Arthritis and
Musculoskeletal and Skin Diseases,
Grant/Award Number: R01AR077518;
National Institutes of Health; Mayo
Foundation for Medical Education and
Research; Mayo Clinic; Lupus Research
Alliance, Grant/Award Number: 696599
第一作者单位：[1]Division of Rheumatology, Department of Medicine, Mayo Clinic Rochester, MN, USA.
通讯作者：
通讯机构：[1]Division of Rheumatology, Department of Medicine, Mayo Clinic Rochester, MN, USA.[7]Department of Immunology, Mayo Clinic Rochester, MN, USA.[*1]Division of Rheumatology, Department of Medicine, Mayo Clinic Rochester, Guggenheim Building 3-42, 200 First ST SW, Rochester, MN 55902, USA.
推荐引用方式(GB/T 7714)：
Zhou Xian,Qi Haiyu,Li Meilu,et al.mTORC2 contributes to systemic autoimmunity[J].Immunology.2022,doi:10.1111/imm.13594.
