Exosomes with membrane-associated TGF-β1 from gene-modified dendritic cells inhibit murine EAE independently of MHC restriction

We have previously demonstrated that exosomes from dendritic cells (DCs) secreting TGF-1 (sTGF-1-EXOs) delay the development of murine inflammatory bowel disease (IBD). In this study, we isolated exosomes from DCs expressing membrane-associated TGF-1 (mTGF-1-EXOs) and found mTGF-1-EXOs had more potent immunosuppressive activity than sTGF-1-EXOs in vitro. Treatment of mice with mTGF-1-EXOs inhibited the development and progression of myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE even after disease onset. Treatment of mice with mTGF-1-EXOs also impaired Ag-specific Th1 and IL-17 responses, but promoted IL-10 responses ex vivo. Treatment with mTGF-1-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-B activation and IL-6 expression in DCs. Treatment with mTGF-1-EXOs maintained the regulatory capacity of Treg cells, and adoptive transfer of CD4(+)Foxp3(+) Treg cells from mTGF-1-EXO-treated EAE mice dramatically prevented the development of EAE in the recipients. Moreover, treatment with mTGF-1-EXOs from C57BL/6 mice effectively prevented and inhibited proteolipid protein (PLP) peptide-induced EAE in BALB/c mice. These results indicate that mTGF-1-EXOs possess powerful immunosuppressive ability and can effectively inhibit the development and progression of EAE in different strains of mice.