title: Exosomes with membrane-associated TGF-β1 from gene-modified dendritic cells inhibit murine EAE independently of MHC restriction.
abstract: We have previously demonstrated that exosomes from dendritic cells (DCs) secreting TGF-β1 (sTGF-β1-EXOs) delay the development of murine inflammatory bowel disease (IBD). In this study, we isolated exosomes from DCs expressing membrane-associated TGF-β1 (mTGF-β1-EXOs) and found mTGF-β1-EXOs had more potent immunosuppressive activity than sTGF-β1-EXOs in vitro. Treatment of mice with mTGF-β1-EXOs inhibited the development and progression of myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE even after disease onset. Treatment of mice with mTGF-β1-EXOs also impaired Ag-specific Th1 and IL-17 responses, but promoted IL-10 responses ex vivo. Treatment with mTGF-β1-EXOs decreased the frequency of Th17 cells in EAE mice, which might be associated with the down-regulation of the p38, ERK, Stat3, and NF-κB activation and IL-6 expression in DCs. Treatment with mTGF-β1-EXOs maintained the regulatory capacity of Treg cells, and adoptive transfer of CD4(+)Foxp3(+)Treg cells from mTGF-β1-EXO-treated EAE mice dramatically prevented the development of EAE in the recipients. Moreover, treatment with mTGF-β1-EXOs from C57BL/6 mice effectively prevented and inhibited proteolipid protein (PLP) peptide-induced EAE in BALB/c mice. These results indicate that mTGF-β1-EXOs possess powerful immunosuppressive ability and can effectively inhibit the development and progression of EAE in different strains of mice.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Fei
authors.initials: F
authors.lastname: Yang
authors.forename: Lingling
authors.initials: L
authors.lastname: Jiang
authors.forename: Yinghu
authors.initials: Y
authors.lastname: Chen
authors.forename: Keyi
authors.initials: K
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.forename: Yinxiang
authors.initials: Y
authors.lastname: Wei
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
authors.forename: Jianli
authors.initials: J
authors.lastname: Wang
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cai
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D004789:Enzyme Activation; D055354:Exosomes / Q000276:immunology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D007165:Immunosuppression Therapy; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000378:metabolism; D016328:NF-kappa B / Q000096:biosynthesis / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000096:biosynthesis / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D015850:Interleukin-6; C571327:Mog protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D049452:Green Fluorescent Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Autoimmune diseases; Exosomes; TGF-β1; Th17; Treg cells