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

Eur J Immunol. 2013 Sep;43(9):2461-72. doi: 10.1002/eji.201243295. Epub 2013 Jun 21.

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; Exosomes; TGF-β1; Th17; Treg cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoimmunity / immunology
  • Cell Proliferation
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control
  • Enzyme Activation
  • Exosomes / immunology*
  • Exosomes / metabolism
  • Extracellular Signal-Regulated MAP Kinases / biosynthesis
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Green Fluorescent Proteins / genetics
  • Immunosuppression
  • Inflammatory Bowel Diseases / immunology
  • Interleukin-10 / metabolism
  • Interleukin-17 / metabolism
  • Interleukin-6 / biosynthesis
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Myelin-Oligodendrocyte Glycoprotein / metabolism
  • NF-kappa B / biosynthesis
  • NF-kappa B / metabolism
  • STAT3 Transcription Factor / biosynthesis
  • STAT3 Transcription Factor / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th17 Cells / immunology
  • Th17 Cells / metabolism
  • Transforming Growth Factor beta1 / immunology*
  • Transforming Growth Factor beta1 / metabolism
  • p38 Mitogen-Activated Protein Kinases / biosynthesis
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Interleukin-17
  • Interleukin-6
  • Mog protein, mouse
  • Myelin-Oligodendrocyte Glycoprotein
  • NF-kappa B
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transforming Growth Factor beta1
  • Interleukin-10
  • Green Fluorescent Proteins
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases