Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling  

作　　者：Runci Wang Meng Hao Xiaoxing Kou Bingdong Sui Maria Laura Sanmillan Xiao Zhang Dawei Liu Jun Tian Wenjing Yu Chider Chen Ruili Yang Lingyun Sun Yi Liu Claudio Giraudo Deepak A.Rao Nan Shen Songtao Shi 

机构地区：[1]Shanghai Institute of Rheumatology/Department of Rheumatology,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,200002,China [2]Department of Anatomy and Cell Biology,School of Dental Medicine,University of Pennsylvania,Philadelphia,PA,19104,USA [3]Department of Rheumatology and Immunology,West China Hospital,Sichuan University,Chengdu,Sichuan,610000,China [4]Division of Rheumatology,Inflammation and Immunity,Brigham and Women’s Hospital and Harvard Medical School,Boston,MA,02105,USA [5]South China Center of Craniofacial Stem Cell Research,Hospital of Stomatology,Guanghua School of Stomatology,Sun Yat-sen University,Guangzhou,Guangdong,510080,China [6]Department of Microbiology and Immunology,Sidney Kimmel Medical College,Thomas Jefferson University,Philadelphia,PA,19107,USA [7]Department of Rheumatology and Immunology,The Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,Jiangsu,210008,China

出　　处：《Bioactive Materials》2023年第7期472-484,共13页生物活性材料（英文）

基　　金：This work was supported by grants from the State Scholarship Fund of China(201506240225to R.W.);the Pearl River Talent Recruitment Program(2019ZT08Y485,2019QN01Y138,2019JC01Y182);the National Key R&D Program of China(2021YFA1100600to S.S.);the Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125,D-07 to S.S.,C-03 and D-11 to X.K.);the National Natural Science Foundation of China(82170924to X.K.).

摘　　要：Mesenchymal stem cells(MSCs)influence T cells in health,disease and therapy through messengers of intercellular communication including extracellular vesicles(EVs).Apoptosis is a mode of cell death that tends to promote immune tolerance,and a large number of apoptotic vesicles(apoVs)are generated from MSCs during apoptosis.In an effort to characterize these apoVs and explore their immunomodulatory potential,here we show that after replenishing them systemically,the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued,leading to the amelioration of inflammation and lupus activity.ApoVs directly interacted with CD4^(+)T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner.A broad range of Th1/2/17 subsets and cytokines including IFNγ,IL17A and IL-10 were suppressed while Foxp3^(+)cells were maintained.Mechanistically,exposed phosphatidylserine(PtdSer/PS)on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction.Remarkably,administration of apoVs prevented Th17 differentiation and memory formation,and ameliorated inflammation and joint erosion in murine arthritis.Collectively,our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4^(+)T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases.

关 键 词：AUTOIMMUNITY T cell MSC Apoptosis Extracellular vesicles 

分 类 号：R593.24[医药卫生—内科学]