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.Keywords: Autoimmune diseases r Exosomes r TGF-β1 r Th17 r Treg cells IntroductionDCs are unique professional APCs and important for the initiation and regulation of immune response [1,2]. Immature DCs have lower levels of co-stimulatory molecules and usually Correspondence: Dr. Zhijian Cai e-mail: caizj@zju.edu.cn; jlwang@zju.edu.cn induce Ag-specific T-cell anergy [3]. TGF-β1 is a negative regulator of pro-inflammatory immune responses. We previously found that systemic administration of TGF-β1 gene-modified immature DCs delayed the development of dextran sulfate sodiuminduced murine inflammatory bowel disease (IBD) [4]. Therefore, * These authors contributed equally to this work. * * These authors share senior co-authorship.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2462 Lei Yu et al. Eur. J. Immunol. 2013. 43: 2461-2472 TGF-β1 may modify DC development toward a regulatory phenotype, inhibiting inflammation. Exosomes, released by almost all types of cells, are small lipid bilayer vesicles with a size of 50-100 nm. They are formed by membrane budding into the lumen of an endocytic compartment, leading to the formation of multivesicular bodies. Fusion of multivesicular bodies to plasma membrane leads to the extracellular release of exosomes [5,6]. Exosomes from DCs transfected with vIL-10, FasL, or IL-4 gene inhibit delayed-type hypersensitivity and collagen-induced murine arthritis [7,8]. These results indicate that exosomes can be effective vehicles to carry immunoregulatory molecules for the treatment of autoimmune diseases.Ag-specific Th1 and Th17 cells are crucial for the development of...

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