Exosomes: composition, biogenesis and function (original) (raw)

• Trams, E. G., Lauter, C. J., Salem, N. Jr & Heine, U. Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim. Biophys. Acta 645, 63–70 (1981).
  Article CAS Google Scholar
• Pan, B. T., Teng, K., Wu, C., Adam, M. & Johnstone, R. M. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J. Cell Biol. 101, 942–948 (1985).
  Article CAS Google Scholar
• Harding, C., Heuser, J. & Stahl, P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J. Cell Biol. 97, 329–339 (1983).References 2 and 3 describe very detailed and careful electron-microscopy analyses of the fate of an endocytosed protein in reticulocytes, and point out, for the first time, the possible secretion of the content of multivesicular late endosomes into the extracellular space.
  Article CAS Google Scholar
• Johnstone, R. M., Adam, M., Hammond, J. R., Orr, L. & Turbide, C. Vesicle formation during reticulocyte maturation. Association of plasma-membrane activities with released vesicles (exosomes). J. Biol. Chem. 262, 9412–9420 (1987).
  CAS PubMed Google Scholar
• Peters, P. J. et al. Molecules relevant for T-cell–target-cell interaction are present in cytolytic granules of human T lymphocytes. Eur. J. Immunol. 19, 1469–1475 (1989).
  Article CAS Google Scholar
• Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).This study shows, for the first time, the secretion of vesicles that are derived from multivesicular late endosomes by an antigen-presenting cell, and the presence of functional MHC class II molecules on the released exosomes.
  Article CAS Google Scholar
• Raposo, G. et al. Accumulation of major histocompatibility complex class II molecules in mast-cell secretory granules and their release upon degranulation. Mol. Biol. Cell 8, 2631–2645 (1997).
  Article CAS Google Scholar
• Zitvogel, L. et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic-cell-derived exosomes. Nature Med. 4, 594–600 (1998).This study shows that exosomes can be secreted by dendritic cells, and that such exosomes can induce antigen-dependent T-cell-mediated immune responses in mice.
  Article CAS Google Scholar
• Thery, C. et al. Molecular characterization of dendritic-cell-derived exosomes. Selective accumulation of the heat-shock protein hsc73. J. Cell Biol. 147, 599–610 (1999).
  Article CAS Google Scholar
• Heijnen, H. F., Schiel, A. E., Fijnheer, R., Geuze, H. J. & Sixma, J. J. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and α-granules. Blood 94, 3791–3799 (1999).
  CAS PubMed Google Scholar
• Davis, J. Q., Dansereau, D., Johnstone, R. M. & Bennett, V. Selective externalization of an ATP-binding protein structurally related to the clathrin-uncoating ATPase/heat-shock protein in vesicles containing terminal transferrin receptors during reticulocyte maturation. J. Biol. Chem. 261, 15368–15371 (1986).
  CAS PubMed Google Scholar
• Thery, C. et al. Proteomic analysis of dendritic-cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J. Immunol. 166, 7309–7318 (2001).A detailed analysis, together with reference 9 , of the protein composition of dendritic-cell-derived exosomes, and a demonstration that they are distinct from apoptotic-cell-derived microvesicles.
  Article CAS Google Scholar
• Skokos, D. et al. Mast-cell-dependent B- and T-lymphocyte activation is mediated by the secretion of immunologically active exosomes. J. Immunol. 166, 868–876 (2001).
  Article CAS Google Scholar
• Martinez-Lorenzo, M. J. et al. Activated human T cells release bioactive Fas ligand and APO2 ligand in microvesicles. J. Immunol. 163, 1274–1281 (1999).
  CAS Google Scholar
• Blanchard, N. et al. TCR activation of human T cells induces the production of exosomes bearing the TCR/CD3/ζ complex. J. Immunol. 168, 3235–3241 (2002).
  Article CAS Google Scholar
• Wolfers, J. et al. Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nature Med. 7, 297–303 (2001).
  Article CAS Google Scholar
• van Niel, G. et al. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology 121, 337–349 (2001).
  Article CAS Google Scholar
• Nilsson, B. O., Lennartsson, L., Carlsson, L., Nilsson, S. & Ronquist, G. Expression of prostasome-like granules by the prostate cancer cell lines PC3, Du145 and LnCaP grown in monolayer. Ups. J. Med. Sci. 104, 199–206 (1999).
  Article CAS Google Scholar
• Hess, C., Sadallah, S., Hefti, A., Landmann, R. & Schifferli, J. A. Ectosomes released by human neutrophils are specialized functional units. J. Immunol. 163, 4564–4573 (1999).
  CAS PubMed Google Scholar
• Mack, M. et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nature Med. 6, 769–775 (2000).
  Article CAS Google Scholar
• MacKenzie, A. et al. Rapid secretion of interleukin-1β by microvesicle shedding. Immunity 15, 825–835 (2001).
  Article CAS Google Scholar
• Escola, J. M. et al. Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B lymphocytes. J. Biol. Chem. 273, 20121–20127 (1998).
  Article CAS Google Scholar
• Rabesandratana, H., Toutant, J. P., Reggio, H. & Vidal, M. Decay-accelerating factor (CD55) and membrane inhibitor of reactive lysis (CD59) are released within exosomes during in vitro maturation of reticulocytes. Blood 91, 2573–2580 (1998).
  CAS PubMed Google Scholar
• Clayton, A. et al. Analysis of antigen-presenting-cell-derived exosomes, based on immuno-magnetic isolation and flow cytometry. J. Immunol. Methods 247, 163–174 (2001).
  Article CAS Google Scholar
• Srivastava, P. Interaction of heat-shock proteins with peptides and antigen-presenting cells: chaperoning of the innate and adaptive immune responses. Annu. Rev. Immunol. 20, 395–425 (2002).
  Article CAS Google Scholar
• Stubbs, J. D. et al. cDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIII-like sequences. Proc. Natl Acad. Sci. USA 87, 8417–8421 (1990).
  Article CAS Google Scholar
• Denzer, K. et al. Follicular dendritic cells carry MHC class-II-expressing microvesicles at their surface. J. Immunol. 165, 1259–1265 (2000).The first direct observation of exosomes in a human tissue (tonsils) in the absence of any in vitro culture step. Most of the other data in this paper, however, are obtained after the in vitro culture of B cells.
  Article CAS Google Scholar
• Mobius, W. et al. Immunoelectron microscopic localization of cholesterol using biotinylated and non-cytolytic perfringolysin O. J. Histochem. Cytochem. 50, 43–55 (2002).
  Article CAS Google Scholar
• Gruenberg, J. & Maxfield, F. R. Membrane transport in the endocytic pathway. Curr. Opin. Cell Biol. 7, 552–563 (1995).
  Article CAS Google Scholar
• Babst, M., Odorizzi, G., Estepa, E. J. & Emr, S. D. Mammalian tumor susceptibility gene 101 (TSG101) and the yeast homologue, Vps23p, both function in late endosomal trafficking. Traffic 1, 248–258 (2000).
  Article CAS Google Scholar
• Vincent-Schneider, H. et al. Exosomes bearing HLA–DR1 molecules need dendritic cells to efficiently stimulate specific T cells. Int. Immunol. 14, 713–722 (2002).
  Article CAS Google Scholar
• Katzmann, D. J., Babst, M. & Emr, S. D. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106, 145–155 (2001).
  Article CAS Google Scholar
• Hicke, L. A new ticket for entry into budding vesicles — ubiquitin. Cell 106, 527–530 (2001).
  Article CAS Google Scholar
• Reggiori, F. & Pelham, H. R. Sorting of proteins into multivesicular bodies: ubiquitin-dependent and -independent targeting. EMBO J. 20, 5176–5186 (2001).
  Article CAS Google Scholar
• Aupeix, K. et al. The significance of shed membrane particles during programmed cell death in vitro, and in vivo, in HIV-1 infection. J. Clin. Invest. 99, 1546–1554 (1997).
  Article CAS Google Scholar
• Mather, I. H. in The Mammary Gland (eds Neville, M. C. & Daniel, C. W.) 217–267 (Plenum, New York, 1987).
  Book Google Scholar
• Peterson, J. A., Patton, S. & Hamosh, M. Glycoproteins of the human milk fat globule in the protection of the breast-fed infant against infections. Biol. Neonate 74, 143–162 (1998).
  Article CAS Google Scholar
• Garrus, J. E. et al. Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. Cell 107, 55–65 (2001).
  Article CAS Google Scholar
• VerPlank, L. et al. Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in HIV type 1 Pr55(Gag). Proc. Natl Acad. Sci. USA 98, 7724–7729 (2001).
  Article CAS Google Scholar
• Martin-Serrano, J., Zang, T. & Bieniasz, P. D. HIV-1 and Ebola virus encode small peptide motifs that recruit Tsg101 to sites of particle assembly to facilitate egress. Nature Med. 7, 1313–1319 (2001).
  Article CAS Google Scholar
• Blott, E. J. & Griffiths, G. M. Secretory lysosomes. Nature Rev. Mol. Cell Biol. 3, 122–131 (2002).
  Article CAS Google Scholar
• Pelham, H. R. SNAREs and the specificity of membrane fusion. Trends Cell Biol. 11, 99–101 (2001).
  Article CAS Google Scholar
• Paumet, F. et al. Soluble NSF attachment protein receptors (SNAREs) in RBL-2H3 mast cells: functional role of syntaxin 4 in exocytosis and identification of a vesicle-associated membrane protein-8-containing secretory compartment. J. Immunol. 164, 5850–5857 (2000).
  Article CAS Google Scholar
• Hibi, T., Hirashima, N. & Nakanishi, M. Rat basophilic leukemia cells express syntaxin-3 and VAMP-7 in granule membranes. Biochem. Biophys. Res. Commun. 271, 36–41 (2000).
  Article CAS Google Scholar
• Guo, Z., Turner, C. & Castle, D. Relocation of the t-SNARE SNAP-23 from lamellipodia-like cell-surface projections regulates compound exocytosis in mast cells. Cell 94, 537–548 (1998).
  Article CAS Google Scholar
• Martinez, I. et al. Synaptotagmin VII regulates Ca2+-dependent exocytosis of lysosomes in fibroblasts. J. Cell Biol. 148, 1141–1149 (2000).
  Article CAS Google Scholar
• Baram, D. et al. Synaptotagmin II negatively regulates Ca2+-triggered exocytosis of lysosomes in mast cells. J. Exp. Med. 189, 1649–1658 (1999).
  Article CAS Google Scholar
• Hwang, I. et al. T cells can use either T-cell receptor or CD28 receptors to absorb and internalize cell-surface molecules derived from antigen-presenting cells. J. Exp. Med. 191, 1137–1148 (2000).
  Article CAS Google Scholar
• Huang, J. F. et al. TCR-mediated internalization of peptide–MHC complexes acquired by T cells. Science 286, 952–954 (1999).
  Article CAS Google Scholar
• Hudrisier, D., Riond, J., Mazarguil, H., Gairin, J. E. & Joly, E. Cutting edge: CTLs rapidly capture membrane fragments from target cells in a TCR signaling-dependent manner. J. Immunol. 166, 3645–3649 (2001).
  Article CAS Google Scholar
• Stinchcombe, J. C., Bossi, G., Booth, S. & Griffiths, G. M. The immunological synapse of CTL contains a secretory domain and membrane bridges. Immunity 15, 751–761 (2001).
  Article CAS Google Scholar
• Brezinschek, R. I., Oppenheimer-Marks, N. & Lipsky, P. E. Activated T cells acquire endothelial cell-surface determinants during transendothelial migration. J. Immunol. 162, 1677–1684 (1999).
  CAS PubMed Google Scholar
• Russo, V. et al. Acquisition of intact allogeneic human leukocyte antigen molecules by human dendritic cells. Blood 95, 3473–3477 (2000).
  CAS PubMed Google Scholar
• Batista, F. D., Iber, D. & Neuberger, M. S. B cells acquire antigen from target cells after synapse formation. Nature 411, 489–494 (2001).
  Article CAS Google Scholar
• Patel, D. M., Arnold, P. Y., White, G. A., Nardella, J. P. & Mannie, M. D. Class II MHC/peptide complexes are released from APC and are acquired by T-cell responders during specific antigen recognition. J. Immunol. 163, 5201–5210 (1999).
  CAS PubMed Google Scholar
• Arnold, P. Y. & Mannie, M. D. Vesicles bearing MHC class II molecules mediate transfer of antigen from antigen-presenting cells to CD4+ T cells. Eur. J. Immunol. 29, 1363–1373 (1999).
  Article CAS Google Scholar
• Bedford, P., Garner, K. & Knight, S. C. MHC class II molecules transferred between allogeneic dendritic cells stimulate primary mixed leukocyte reactions. Int. Immunol. 11, 1739–1744 (1999).
  Article CAS Google Scholar
• Knight, S. C., Iqball, S., Roberts, M. S., Macatonia, S. & Bedford, P. A. Transfer of antigen between dendritic cells in the stimulation of primary T-cell proliferation. Eur. J. Immunol. 28, 1636–1644 (1998).
  Article CAS Google Scholar
• Sharrow, S. O., Mathieson, B. J. & Singer, A. Cell-surface appearance of unexpected host MHC determinants on thymocytes from radiation bone-marrow chimeras. J. Immunol. 126, 1327–1335 (1981).
  CAS PubMed Google Scholar
• Gray, D., Kosco, M. & Stockinger, B. Novel pathways of antigen presentation for the maintenance of memory. Int. Immunol. 3, 141–148 (1991).
  Article CAS Google Scholar
• Greco, V., Hannus, M. & Eaton, S. Argosomes: a potential vehicle for the spread of morphogens through epithelia. Cell 106, 633–645 (2001).This study shows a visualization in vivo in embryonic tissues of the transfer of membrane structures that are labelled with a fluorescent lipid between adjacent cells. The membrane structures that are involved have not been characterized.
  Article CAS Google Scholar
• Pan, B. T. & Johnstone, R. M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33, 967–978 (1983).
  Article CAS Google Scholar
• Karlsson, M. et al. 'Tolerosomes' are produced by intestinal epithelial cells. Eur. J. Immunol. 31, 2892–2900 (2001).
  Article CAS Google Scholar
• Dukers, D. F. et al. Direct immunosuppressive effects of EBV-encoded latent membrane protein 1. J. Immunol. 165, 663–670 (2000).
  Article CAS Google Scholar
• Monleon, I. et al. Differential secretion of Fas ligand- or APO2 ligand/TNF-related apoptosis-inducing ligand-carrying microvesicles during activation-induced death of human T cells. J. Immunol. 167, 6736–6744 (2001).
  Article CAS Google Scholar
• Andreola, G. et al. Induction of lymphocyte apoptosis by tumor-cell secretion of FasL-bearing microvesicles. J. Exp. Med. 195, 1303–1316 (2002).
  Article CAS Google Scholar
• André, F. et al. Malignant ascitis accumulate immunogenic tumor-derived exosomes: novel approach for cancer immunotherapy. Lancet (in the press).
• Kleijmeer, M. J. et al. Antigen loading of MHC class I molecules in the endocytic tract. Traffic 2, 124–137 (2001).
  Article CAS Google Scholar
• Rieu, S., Geminard, C., Rabesandratana, H., Sainte-Marie, J. & Vidal, M. Exosomes released during reticulocyte maturation bind to fibronectin via integrin α4β1. Eur. J. Biochem. 267, 583–590 (2000).
  Article CAS Google Scholar