Exosome Secretion: Molecular Mechanisms and Roles in Immune Responses

Exosomes are small membrane vesicles, secreted by most cell types from multivesicular endosomes, and thought to play important roles in intercellular communications. Initially described in 1983, as specifically secreted by reticulocytes, exosomes became of interest for immunologists in 1996, when they were proposed to play a role in antigen presentation. More recently, the finding that exosomes carry genetic materials, mRNA and miRNA, has been a major breakthrough in the field, unveiling their capacity to vehicle genetic messages. It is now clear that not only immune cells but probably all cell types are able to secrete exosomes: their range of possible functions expands well beyond immunology to neurobiology, stem cell and tumor biology, and their use in clinical applications as biomarkers or as therapeutic tools is an extensive area of research. Despite intensive efforts to understand their functions, two issues remain to be solved in the future: (i) what are the physiological function(s) of exosomes in vivo and (ii) what are the relative contributions of exosomes and of other secreted membrane vesicles in these proposed functions? Here, we will focus on the current ideas on exosomes and immune responses, but also on their mechanisms of secretion and the use of this knowledge to elucidate the latter issue.

[1]  S. Pomeroy,et al.  Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. , 2011, Nature communications.

[2]  Laurence Zitvogel,et al.  Molecular Characterization of Dendritic Cell-Derived Exosomes , 1999, The Journal of cell biology.

[3]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[4]  I. Brody,et al.  The prostasome: its secretion and function in man. , 1985, Biochimica et biophysica acta.

[5]  Jacopo Meldolesi,et al.  Shedding microvesicles: artefacts no more. , 2009, Trends in cell biology.

[6]  P. Ricciardi-Castagnoli,et al.  Proteomic Analysis of Dendritic Cell-Derived Exosomes: A Secreted Subcellular Compartment Distinct from Apoptotic Vesicles1 , 2001, The Journal of Immunology.

[7]  C. Théry,et al.  Indirect activation of naïve CD4+ T cells by dendritic cell–derived exosomes , 2002, Nature Immunology.

[8]  L. Zitvogel,et al.  Exosomes as Potent Cell-Free Peptide-Based Vaccine. II. Exosomes in CpG Adjuvants Efficiently Prime Naive Tc1 Lymphocytes Leading to Tumor Rejection 1 , 2004, The Journal of Immunology.

[9]  S. Gould,et al.  Higher-Order Oligomerization Targets Plasma Membrane Proteins and HIV Gag to Exosomes , 2007, PLoS biology.

[10]  Gerard Pasterkamp,et al.  Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. , 2010, Stem cell research.

[11]  R. Legouis,et al.  Developmental and cellular functions of the ESCRT machinery in pluricellular organisms , 2010, Biology of the cell.

[12]  L. Zitvogel,et al.  Updated Technology to Produce Highly Immunogenic Dendritic Cell-derived Exosomes of Clinical Grade: A Critical Role of Interferon-&ggr; , 2011, Journal of immunotherapy.

[13]  L. Zitvogel,et al.  Exosomes as Potent Cell-Free Peptide-Based Vaccine. I. Dendritic Cell-Derived Exosomes Transfer Functional MHC Class I/Peptide Complexes to Dendritic Cells 1 , 2004, The Journal of Immunology.

[14]  Veronica Huber,et al.  Induction of Lymphocyte Apoptosis by Tumor Cell Secretion of FasL-bearing Microvesicles , 2002, The Journal of experimental medicine.

[15]  Simon C Watkins,et al.  Exosomes As a Short-Range Mechanism to Spread Alloantigen between Dendritic Cells during T Cell Allorecognition1 , 2008, The Journal of Immunology.

[16]  C. Théry,et al.  Exosomes from Bronchoalveolar Fluid of Tolerized Mice Prevent Allergic Reaction1 , 2008, The Journal of Immunology.

[17]  S. Gabrielsson,et al.  Direct exosome stimulation of peripheral humanT cells detected by ELISPOT , 2006, European journal of immunology.

[18]  Fátima Sánchez-Cabo,et al.  Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells , 2011, Nature communications.

[19]  G. Raposo,et al.  A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. , 2006, Developmental cell.

[20]  M. Vidal,et al.  Exosome Release Is Regulated by a Calcium-dependent Mechanism in K562 Cells* , 2003, Journal of Biological Chemistry.

[21]  Jing Li,et al.  Secreted monocytic miR-150 enhances targeted endothelial cell migration. , 2010, Molecular cell.

[22]  Alzheimer's disease beta-amyloid peptides are released in association with exosomes. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[23]  G. Cagney,et al.  HIV Nef is Secreted in Exosomes and Triggers Apoptosis in Bystander CD4+ T Cells , 2010, Traffic.

[24]  Willem Stoorvogel,et al.  Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. , 2009, Blood.

[25]  Riitta Lahesmaa,et al.  Exosomes with Immune Modulatory Features Are Present in Human Breast Milk1 , 2007, The Journal of Immunology.

[26]  Laurence Zitvogel,et al.  Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming , 2001, Nature Medicine.

[27]  S. Kaushal,et al.  Journal of Translational Medicine BioMed Central , 2008 .

[28]  M. Mason,et al.  Human Tumor-Derived Exosomes Down-Modulate NKG2D Expression1 , 2008, The Journal of Immunology.

[29]  C. Melief,et al.  B lymphocytes secrete antigen-presenting vesicles , 1996, The Journal of experimental medicine.

[30]  P. Robbins,et al.  Therapeutic effect of exosomes from indoleamine 2,3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models. , 2009, Arthritis and rheumatism.

[31]  T. Whiteside,et al.  Tumor-Derived Microvesicles Induce, Expand and Up-Regulate Biological Activities of Human Regulatory T Cells (Treg) , 2010, PloS one.

[32]  Jessica A. Weber,et al.  Export of microRNAs and microRNA-protective protein by mammalian cells , 2010, Nucleic acids research.

[33]  Hamid Cheshmi Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers , 2011 .

[34]  Clotilde Théry,et al.  Exosomes: immune properties and potential clinical implementations , 2011, Seminars in Immunopathology.

[35]  Sibel Akyol,et al.  Pregnancy-Associated Exosomes and Their Modulation of T Cell Signaling1 , 2006, The Journal of Immunology.

[36]  M. T. Damiani,et al.  Rab11 Promotes Docking and Fusion of Multivesicular Bodies in a Calcium‐Dependent Manner , 2005, Traffic.

[37]  Miguel C. Seabra,et al.  Rab27a and Rab27b control different steps of the exosome secretion pathway , 2010, Nature Cell Biology.

[38]  C. Hess,et al.  Ectosomes released by human neutrophils are specialized functional units. , 1998, Journal of immunology.

[39]  A. Muntasell,et al.  T cell‐induced secretion of MHC class II–peptide complexes on B cell exosomes , 2007, The EMBO journal.

[40]  J. Slot,et al.  Proteomic and Biochemical Analyses of Human B Cell-derived Exosomes , 2003, The Journal of Biological Chemistry.

[41]  M. Adam,et al.  Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes , 1985, The Journal of cell biology.

[42]  G. Lachenal,et al.  Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity , 2011, Molecular and Cellular Neuroscience.

[43]  Taoyong Chen,et al.  More Efficient Induction of HLA-A*0201-Restricted and Carcinoembryonic Antigen (CEA)–Specific CTL Response by Immunization with Exosomes Prepared from Heat-Stressed CEA-Positive Tumor Cells , 2005, Clinical Cancer Research.

[44]  S. Gabrielsson,et al.  Antigen-loaded exosomes alone induce Th1-type memory through a B-cell-dependent mechanism. , 2009, Blood.

[45]  W. Faigle,et al.  Cells release prions in association with exosomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  T. D. de Gruijl,et al.  Functional delivery of viral miRNAs via exosomes , 2010, Proceedings of the National Academy of Sciences.

[47]  L. Mincheva-Nilsson,et al.  Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function1 , 2009, The Journal of Immunology.

[48]  C. Huynh,et al.  Identification of SNAREs Involved in Synaptotagmin VII-regulated Lysosomal Exocytosis* , 2004, Journal of Biological Chemistry.

[49]  A. Villa,et al.  Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. , 2006, Cancer research.

[50]  C. Théry,et al.  Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses. , 2008, Cancer research.

[51]  Simon C Watkins,et al.  Exosomes Derived from IL-10-Treated Dendritic Cells Can Suppress Inflammation and Collagen-Induced Arthritis 1 , 2005, The Journal of Immunology.

[52]  L. Foster,et al.  Leishmania Exosomes Modulate Innate and Adaptive Immune Responses through Effects on Monocytes and Dendritic Cells , 2010, The Journal of Immunology.

[53]  E. Telemo,et al.  Tolerosome‐induced oral tolerance is MHC dependent , 2005, Immunology.

[54]  Laurence Zitvogel,et al.  Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell derived exosomes , 1998, Nature Medicine.

[55]  A. Booth,et al.  Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane , 2006, The Journal of cell biology.

[56]  J. Pober,et al.  Cytomegalovirus-Infected Human Endothelial Cells Can Stimulate Allogeneic CD4+ Memory T Cells by Releasing Antigenic Exosomes1 , 2009, The Journal of Immunology.

[57]  G. Parmiani,et al.  Tumour-released exosomes and their implications in cancer immunity , 2008, Cell Death and Differentiation.

[58]  Aled Clayton,et al.  Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. , 2007, Cancer research.

[59]  E. Tomaskovic-Crook,et al.  Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice , 2003, Gut.

[60]  A. Guha,et al.  Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells , 2008, Nature Cell Biology.

[61]  T. Whiteside,et al.  T-cell apoptosis and suppression of T-cell receptor/CD3-zeta by Fas ligand-containing membrane vesicles shed from ovarian tumors. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[62]  E. Kroh,et al.  Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma , 2011, Proceedings of the National Academy of Sciences.

[63]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[64]  Petra Schwille,et al.  Ceramide Triggers Budding of Exosome Vesicles into Multivesicular Endosomes , 2008, Science.

[65]  W. Möbius,et al.  Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C , 2010, The Journal of cell biology.

[66]  R. Johnstone,et al.  Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). , 1987, The Journal of biological chemistry.

[67]  Aled Clayton,et al.  Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids , 2006, Current protocols in cell biology.

[68]  J. Casado,et al.  Human prostasomes express CD48 and interfere with NK cell function. , 2011, Immunobiology.

[69]  N. Tanaka,et al.  Exosome secretion of dendritic cells is regulated by Hrs, an ESCRT-0 protein. , 2010, Biochemical and biophysical research communications.

[70]  N. Hogg,et al.  CD8+ Dendritic Cells Use LFA-1 to Capture MHC-Peptide Complexes from Exosomes In Vivo1 , 2007, The Journal of Immunology.

[71]  Stefan Matile,et al.  Role of LBPA and Alix in Multivesicular Liposome Formation and Endosome Organization , 2004, Science.

[72]  S. Mathivanan,et al.  ExoCarta: A compendium of exosomal proteins and RNA , 2009, Proteomics.

[73]  Rong-Fong Shen,et al.  Identification and proteomic profiling of exosomes in human urine. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[74]  P. Stahl,et al.  Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes , 1983, The Journal of cell biology.

[75]  J Ratajczak,et al.  Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery , 2006, Leukemia.

[76]  W. Stoorvogel,et al.  Exosomes contain ubiquitinated proteins. , 2005, Blood cells, molecules & diseases.

[77]  L. Santambrogio,et al.  Proteomic Analysis of Microglia-Derived Exosomes: Metabolic Role of the Aminopeptidase CD13 in Neuropeptide Catabolism1 , 2005, The Journal of Immunology.

[78]  V. Dolo,et al.  Modulation of vesicle shedding in 8701 BC human breast carcinoma cells. , 1998, Journal of submicroscopic cytology and pathology.

[79]  C. Melief,et al.  MHC II in Dendritic Cells is Targeted to Lysosomes or T Cell‐Induced Exosomes Via Distinct Multivesicular Body Pathways , 2009, Traffic.

[80]  S. Tenzer,et al.  Oligodendrocytes secrete exosomes containing major myelin and stress‐protective proteins: Trophic support for axons? , 2007, Proteomics. Clinical applications.

[81]  G. Parmiani,et al.  Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. , 2005, Gastroenterology.

[82]  J. Luzio,et al.  Ectocytosis caused by sublytic autologous complement attack on human neutrophils. The sorting of endogenous plasma-membrane proteins and lipids into shed vesicles. , 1991, The Biochemical journal.

[83]  Sanchita Bhatnagar,et al.  Exosomes Released from Infected Macrophages Contain Mycobacterium avium Glycopeptidolipids and Are Proinflammatory* , 2007, Journal of Biological Chemistry.

[84]  M. Babst A Protein's Final ESCRT , 2005, Traffic.

[85]  M. Bevan,et al.  Cross-dressed dendritic cells drive memory CD8+ T-cell activation after viral infection , 2011, Nature.

[86]  Simon C Watkins,et al.  Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. , 2004, Blood.

[87]  W. Grizzle,et al.  TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes. , 2010, The American journal of pathology.

[88]  William E. Grizzle,et al.  Murine Mammary Carcinoma Exosomes Promote Tumor Growth by Suppression of NK Cell Function1 , 2006, The Journal of Immunology.

[89]  C. Théry,et al.  ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. , 2005, Blood.

[90]  Taoyong Chen,et al.  Enhanced induction of dendritic cell maturation and HLA-A*0201-restricted CEA-specific CD8+ CTL response by exosomes derived from IL-18 gene-modified CEA-positive tumor cells , 2006, Journal of Molecular Medicine.

[91]  Cicek Gercel-Taylor,et al.  MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. , 2008, Gynecologic oncology.

[92]  A. Molinari,et al.  Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells* , 2009, The Journal of Biological Chemistry.

[93]  C. Usal,et al.  Presentation of donor major histocompatibility complex antigens by bone marrow dendritic cell-derived exosomes modulates allograft rejection1 , 2003, Transplantation.