Exosomes: immune properties and potential clinical implementations

Springer Science and Business Media LLC - Tập 33 Số 5 - Trang 419-440 - 2011
Nathalie Chaput1, Clotilde Théry2
1Institut National de la Santé et de la Recherche Médicale U1015, Villejuif, 94805, France
2Institut Curie, Paris 75005, France

Tóm tắt

Từ khóa


Tài liệu tham khảo

Adachi J, Kumar C, Zhang Y, Olsen JV, Mann M (2006) The human urinary proteome contains more than 1500 proteins, including a large proportion of membrane proteins. Genome Biol 7:R80

Adams M, Navabi H, Croston D, Coleman S, Tabi Z, Clayton A, Jasani B, Mason MD (2005) The rationale for combined chemo/immunotherapy using a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer. Vaccine 23:2374–2378

Admyre C, Bohle B, Johansson SM, Focke-Tejkl M, Valenta R, Scheynius A, Gabrielsson S (2007) B cell-derived exosomes can present allergen peptides and activate allergen-specific T cells to proliferate and produce TH2-like cytokines. J Allergy Clin Immunol 120:1418–1424

Admyre C, Grunewald J, Thyberg J, Gripenback S, Tornling G, Eklund A, Scheynius A, Gabrielsson S (2003) Exosomes with major histocompatibility complex class II and co-stimulatory molecules are present in human BAL fluid. Eur Respir J 22:578–583

Admyre C, Johansson SM, Paulie S, Gabrielsson S (2006) Direct exosome stimulation of peripheral human T cells detected by ELISPOT. Eur J Immunol 36:1772–1781

Admyre C, Johansson SM, Qazi KR, Filen JJ, Lahesmaa R, Norman M, Neve EP, Scheynius A, Gabrielsson S (2007) Exosomes with immune modulatory features are present in human breast milk. J Immunol 179:1969–1978

Al-Nedawi K, Meehan B, Kerbel RS, Allison AC, Rak J (2009) Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc Natl Acad Sci USA 106:3794–3799

Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, Rak J (2008) Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol 10:619–624

Aline F, Bout D, Amigorena S, Roingeard P, Dimier-Poisson I (2004) Toxoplasma gondii antigen-pulsed-dendritic cell-derived exosomes induce a protective immune response against T. gondii infection. Infect Immun 72:4127–4137

Allan RS, Waithman J, Bedoui S, Jones CM, Villadangos JA, Zhan Y, Lew AM, Shortman K, Heath WR, Carbone FR (2006) Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity 25:153–162

Alonso R, Rodriguez MC, Pindado J, Merino E, Merida I, Izquierdo M (2005) Diacylglycerol kinase alpha regulates the secretion of lethal exosomes bearing Fas ligand during activation-induced cell death of T lymphocytes. J Biol Chem 280:28439–28450

Andre F, Chaput N, Schartz NE, Flament C, Aubert N, Bernard J, Lemonnier F, Raposo G, Escudier B, Hsu DH, Tursz T, Amigorena S, Angevin E, Zitvogel L (2004) Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol 172:2126–2136

Andre F, Schartz NE, Movassagh M, Flament C, Pautier P, Morice P, Pomel C, Lhomme C, Escudier B, Le Chevalier T, Tursz T, Amigorena S, Raposo G, Angevin E, Zitvogel L (2002) Malignant effusions and immunogenic tumour-derived exosomes. Lancet 360:295–305

Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, Squarcina P, Accornero P, Lozupone F, Lugini L, Stringaro A, Molinari A, Arancia G, Gentile M, Parmiani G, Fais S (2002) Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. J Exp Med 195:1303–1316

Andrews NW, Chakrabarti S (2005) There’s more to life than neurotransmission: the regulation of exocytosis by synaptotagmin VII. Trends Cell Biol 15:626–631

Asea A, Jean-Pierre C, Kaur P, Rao P, Linhares IM, Skupski D, Witkin SS (2008) Heat shock protein-containing exosomes in mid-trimester amniotic fluids. J Reprod Immunol 79:12–17

Ashiru O, Boutet P, Fernandez-Messina L, Aguera-Gonzalez S, Skepper JN, Vales-Gomez M, Reyburn HT (2010) Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes. Cancer Res 70:481–489

Baj-Krzyworzeka M, Szatanek R, Weglarczyk K, Baran J, Urbanowicz B, Branski P, Ratajczak MZ, Zembala M (2006) Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytes. Cancer Immunol Immunother 55:808–818

Bard MP, Hegmans JP, Hemmes A, Luider TM, Willemsen R, Severijnen LA, van Meerbeeck JP, Burgers SA, Hoogsteden HC, Lambrecht BN (2004) Proteomic analysis of exosomes isolated from human malignant pleural effusions. Am J Respir Cell Mol Biol 31:114–121

Barres C, Blanc L, Bette-Bobillo P, Andre S, Mamoun R, Gabius HJ, Vidal M (2010) Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood 115:696–705

Beauvillain C, Juste MO, Dion S, Pierre J, Dimier-Poisson I (2009) Exosomes are an effective vaccine against congenital toxoplasmosis in mice. Vaccine 27:1750–1757

Beauvillain C, Ruiz S, Guiton R, Bout D, Dimier-Poisson I (2007) A vaccine based on exosomes secreted by a dendritic cell line confers protection against T. gondii infection in syngeneic and allogeneic mice. Microbes Infect 9:1614–1622

Bergmann C, Strauss L, Wieckowski E, Czystowska M, Albers A, Wang Y, Zeidler R, Lang S, Whiteside TL (2009) Tumor-derived microvesicles in sera of patients with head and neck cancer and their role in tumor progression. Head Neck 31:371–380

Bhatnagar S, Schorey JS (2007) Exosomes released from infected macrophages contain mycobacterium avium glycopeptidolipids and are proinflammatory. J Biol Chem 282:25779–25789

Bhatnagar S, Shinagawa K, Castellino FJ, Schorey JS (2007) Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 110:3234–3244

Bianco NR, Kim SH, Ruffner MA, Robbins PD (2009) Therapeutic effect of exosomes from indoleamine 2, 3-dioxygenase-positive dendritic cells in collagen-induced arthritis and delayed-type hypersensitivity disease models. Arthritis Rheum 60:380–389

Booth AM, Fang Y, Fallon JK, Yang JM, Hildreth JE, Gould SJ (2006) Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol 172:923–935

Buschow SI, Nolte-’t Hoen EN, van Niel G, Pols MS, Ten Broeke T, Lauwen M, Ossendorp F, Melief CJ, Raposo G, Wubbolts R, Wauben MH, Stoorvogel W (2009) MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10(10):1528–1542

Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal-like vesicles are present in human blood plasma. Int Immunol 17:879–887

Cantin R, Diou J, Belanger D, Tremblay AM, Gilbert C (2008) Discrimination between exosomes and HIV-1: purification of both vesicles from cell-free supernatants. J Immunol Meth 338:21–30

Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin JP, Boireau W, Rouleau A, Simon B, Lanneau D, De Thonel A, Multhoff G, Hamman A, Martin F, Chauffert B, Solary E, Zitvogel L, Garrido C, Ryffel B, Borg C, Apetoh L, Rebe C, Ghiringhelli F (2010) Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest 120:457–471

Chaput N, Schartz NE, Andre F, Taieb J, Novault S, Bonnaventure P, Aubert N, Bernard J, Lemonnier F, Merad M, Adema G, Adams M, Ferrantini M, Carpentier AF, Escudier B, Tursz T, Angevin E, Zitvogel L (2004) Exosomes as potent cell-free peptide-based vaccine. II. Exosomes in CpG adjuvants efficiently prime naive Tc1 lymphocytes leading to tumor rejection. J Immunol 172:2137–2146

Chavez-Munoz C, Morse J, Kilani R, Ghahary A (2008) Primary human keratinocytes externalize stratifin protein via exosomes. J Cell Biochem 104:2165–2173

Chen C, Skog J, Hsu CH, Lessard RT, Balaj L, Wurdinger T, Carter BS, Breakefield XO, Toner M, Irimia D (2010) Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip 10:505–511

Cho JA, Lee YS, Kim SH, Ko JK, Kim CW (2009) MHC independent anti-tumor immune responses induced by Hsp70-enriched exosomes generate tumor regression in murine models. Cancer Lett 275:256–265

Clayton A, Court J, Navabi H, Adams M, Mason MD, Hobot JA, Newman GR, Jasani B (2001) Analysis of antigen presenting cell derived exosomes, based on immuno-magnetic isolation and flow cytometry. J Immunol Meth 247:163–174

Clayton A, Harris CL, Court J, Mason MD, Morgan BP (2003) Antigen-presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59. Eur J Immunol 33:522–531

Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z (2008) Human tumor-derived exosomes down-modulate NKG2D expression. J Immunol 180:7249–7258

Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z (2007) Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 67:7458–7466

Clayton A, Turkes A, Navabi H, Mason MD, Tabi Z (2005) Induction of heat shock proteins in B-cell exosomes. J Cell Sci 118:3631–3638

Colino J, Snapper CM (2006) Exosomes from bone marrow dendritic cells pulsed with diphtheria toxoid preferentially induce type 1 antigen-specific IgG responses in naive recipients in the absence of free antigen. J Immunol 177:3757–3762

Czystowska M, Han J, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, Hadden JW, Signorelli K, Whiteside TL (2009) IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death. Cell Death Differ 16:708–718

Dai S, Wan T, Wang B, Zhou X, Xiu F, Chen T, Wu Y, Cao X (2005) 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. Clin Cancer Res 11:7554–7563

Dai S, Wei D, Wu Z, Zhou X, Wei X, Huang H, Li G (2008) Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 16:782–790

Dai S, Zhou X, Wang B, Wang Q, Fu Y, Chen T, Wan T, Yu Y, Cao X (2006) 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. J Mol Med 84:1067–1076

de Gassart A, Geminard C, Fevrier B, Raposo G, Vidal M (2003) Lipid raft-associated protein sorting in exosomes. Blood 102:4336–4344

De La Pena H, Madrigal JA, Rusakiewicz S, Bencsik M, Cave GW, Selman A, Rees RC, Travers PJ, Dodi IA (2009) Artificial exosomes as tools for basic and clinical immunology. J Immunol Meth 344:121–132

De Smaele E, Ferretti E, Gulino A (2010) MiRNAs as biomarkers for CNS cancer and other disorders. Brain Res 1338:100–111

Denzer K, van Eijk M, Kleijmeer MJ, Jakobson E, de Groot C, Geuze HJ (2000) Follicular dendritic cells carry MHC class II-expressing microvesicles at their surface. J Immunol 165:1259–1265

Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, Bruno S, Bussolati B, Camussi G (2007) Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood 110:2440–2448

Escudier B, Dorval T, Chaput N, Andre F, Caby MP, Novault S, Flament C, Leboulaire C, Borg C, Amigorena S, Boccaccio C, Bonnerot C, Dhellin O, Movassagh M, Piperno S, Robert C, Serra V, Valente N, Le Pecq JB, Spatz A, Lantz O, Tursz T, Angevin E, Zitvogel L (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst phase I clinical trial. J Transl Med 3:10

Faure J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, Grange J, Schoehn G, Goldberg Y, Boyer V, Kirchhoff F, Raposo G, Garin J, Sadoul R (2006) Exosomes are released by cultured cortical neurones. Mol Cell Neurosci 31:642–648

Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H, Raposo G (2004) Cells release prions in association with exosomes. Proc Natl Acad Sci USA 101:9683–9688

Flanagan J, Middeldorp J, Sculley T (2003) Localization of the Epstein-Barr virus protein LMP 1 to exosomes. J Gen Virol 84:1871–1879

Fleeton MN, Contractor N, Leon F, Wetzel JD, Dermody TS, Kelsall BL (2004) Peyer’s patch dendritic cells process viral antigen from apoptotic epithelial cells in the intestine of reovirus-infected mice. J Exp Med 200:235–245

Fortin JF, Cantin R, Tremblay MJ (1998) T cells expressing activated LFA-1 are more susceptible to infection with human immunodeficiency virus type 1 particles bearing host-encoded ICAM-1. J Virol 72:2105–2112

Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247

Gatti JL, Metayer S, Belghazi M, Dacheux F, Dacheux JL (2005) Identification, proteomic profiling, and origin of ram epididymal fluid exosome-like vesicles. Biol Reprod 72:1452–1465

GeurtsvanKessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, Baas C, Thielemans K, Bennett C, Clausen BE, Hoogsteden HC, Osterhaus AD, Rimmelzwaan GF, Lambrecht BN (2008) Clearance of influenza virus from the lung depends on migratory langerin + CD11b- but not plasmacytoid dendritic cells. J Exp Med 205:1621–1634

Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B (2007) Metronomic cyclophosphamide regimen selectively depletes CD4 + CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56:641–648

Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O (2009) Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol 11:1143–1149

Giri PK, Kruh NA, Dobos KM, Schorey JS (2010) Proteomic analysis identifies highly antigenic proteins in exosomes from M. tuberculosis-infected and culture filtrate protein-treated macrophages. Proteomics 10:3190–3202

Giri PK, Schorey JS (2008) Exosomes derived from M. bovis BCG infected macrophages activate antigen-specific CD4+ and CD8+ T cells in vitro and in vivo. PLoS ONE 3:e2461

Gonzalez-Begne M, Lu B, Han X, Hagen FK, Hand AR, Melvin JE, Yates JR (2009) Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). J Proteome Res 8:1304–1314

Graner MW, Alzate O, Dechkovskaia AM, Keene JD, Sampson JH, Mitchell DA, Bigner DD (2009) Proteomic and immunologic analyses of brain tumor exosomes. FASEB J 23:1541–1557

Guescini M, Genedani S, Stocchi V, Agnati LF (2010) Astrocytes and Glioblastoma cells release exosomes carrying mtDNA. J Neural Transm 117:1–4

Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–187

Harding C, Heuser J, Stahl P (1983) Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol 97:329–339

Hata T, Murakami K, Nakatani H, Yamamoto Y, Matsuda T, Aoki N (2010) Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. Biochem Biophys Res Commun 396:528–533

Hawari FI, Rouhani FN, Cui X, Yu ZX, Buckley C, Kaler M, Levine SJ (2004) Release of full-length 55-kDa TNF receptor 1 in exosome-like vesicles: a mechanism for generation of soluble cytokine receptors. Proc Natl Acad Sci USA 101:1297–1302

Hedlund M, Stenqvist AC, Nagaeva O, Kjellberg L, Wulff M, Baranov V, Mincheva-Nilsson L (2009) Human placenta expresses and secretes NKG2D ligands via exosomes that down-modulate the cognate receptor expression: evidence for immunosuppressive function. J Immunol 183:340–351

Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ (1999) Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood 94:3791–3799

Hess C, Sadallah S, Hefti A, Landmann R, Schifferli JA (1999) Ectosomes released by human neutrophils are specialized functional units. J Immunol 163:4564–4573

Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L, Provost N, Frohlich MW (2009) Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 115:3670–3679

Hsu C, Morohashi Y, Yoshimura S, Manrique-Hoyos N, Jung S, Lauterbach MA, Bakhti M, Gronborg M, Möbius W, Rhee J, Barr FA, Simons M (2010) Regulation of exosome secretion by Rab35 and its GTPase-activaitng proteins TBC1D10A-C. J Cell Biol 189:223–232

Hsu DH, Paz P, Villaflor G, Rivas A, Mehta-Damani A, Angevin E, Zitvogel L, Le Pecq JB (2003) Exosomes as a tumor vaccine: enhancing potency through direct loading of antigenic peptides. J Immunother 26:440–450

Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P, Zaccheddu A, Colone M, Arancia G, Gentile M, Seregni E, Valenti R, Ballabio G, Belli F, Leo E, Parmiani G, Rivoltini L (2005) Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology 128:1796–1804

Hume AN, Collinson LM, Rapak A, Gomes AQ, Hopkins CR, Seabra MC (2001) Rab27a regulates the peripheral distribution of melanosomes in melanocytes. J Cell Biol 152:795–808

Iero M, Valenti R, Huber V, Filipazzi P, Parmiani G, Fais S, Rivoltini L (2008) Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ 15:80–88

Iliev DB, Jorgensen SM, Rode M, Krasnov A, Harneshaug I, Jorgensen JB (2010) CpG-induced secretion of MHCIIbeta and exosomes from salmon (Salmo salar) APCs. Dev Comp Immunol 34:29–41

Islam A, Shen X, Hiroi T, Moss J, Vaughan M, Levine SJ (2007) The brefeldin A-inhibited guanine nucleotide-exchange protein, BIG2, regulates the constitutive release of TNFR1 exosome-like vesicles. J Biol Chem 282:9591–9599

Izquierdo-Useros N, Naranjo-Gomez M, Archer J, Hatch SC, Erkizia I, Blanco J, Borras FE, Puertas MC, Connor JH, Fernandez-Figueras MT, Moore L, Clotet B, Gummuluru S, Martinez-Picado J (2009) Capture and transfer of HIV-1 particles by mature dendritic cells converges with the exosome-dissemination pathway. Blood 113:2732–2741

Jansen FH, Krijgsveld J, van Rijswijk A, van den Bemd GJ, van den Berg MS, van Weerden WM, Willemsen R, Dekker LJ, Luider TM, Jenster G (2009) Exosomal secretion of cytoplasmic prostate cancer xenograft-derived proteins. Mol Cell Proteomics 8:1192–1205

Jinushi M, Nakazaki Y, Dougan M, Carrasco DR, Mihm M, Dranoff G (2007) MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF. J Clin Invest 117:1902–1913

Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C (1987) Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem 262:9412–9420

Johnstone RM, Mathew A, Mason AB, Teng K (1991) Exosome formation during maturation of mammalian and avian reticulocytes: evidence that exosome release is a major route for externalization of obsolete membrane proteins. J Cell Physiol 147:27–36

Jung T, Castellana D, Klingbeil P, Hernandez IC, Vitacolonna M, Orlicky DJ, Roffler SR, Brodt P, Zoller M (2009) CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11:1093–1105

Karlsson M, Lundin S, Dahlgren U, Kahu H, Pettersson I, Telemo E (2001) “Tolerosomes” are produced by intestinal epithelial cells. Eur J Immunol 31:2892–2900

Kassis S, Lauter CJ, Stojanov M, Salem N Jr (1986) Exfoliation of the beta-adrenergic receptor and the regulatory components of adenylate cyclase by cultured rat glioma C6 cells. Biochim Biophys Acta 886:474–482

Katzmann DJ, Odorizzi G, Emr SD (2002) Receptor downregulation and multivesicular-body sorting. Nat Rev Mol Cell Biol 3:893–905

Keller S, Konig AK, Marme F, Runz S, Wolterink S, Koensgen D, Mustea A, Sehouli J, Altevogt P (2009) Systemic presence and tumor-growth promoting effect of ovarian carcinoma released exosomes. Cancer Lett 278:73–81

Keryer-Bibens C, Pioche-Durieu C, Villemant C, Souquere S, Nishi N, Hirashima M, Middeldorp J, Busson P (2006) Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral latent membrane protein 1 and the immunomodulatory protein galectin 9. BMC Cancer 6:283

Kesimer M, Scull M, Brighton B, Demaria G, Burns K, O'Neal W, Pickles RJ, Sheehan JK (2009) Characterization of exosome-like vesicles released from human tracheobronchial ciliated epithelium: a possible role in innate defense. FASEB J 23:1858–1868

Kim JW, Wieckowski E, Taylor DD, Reichert TE, Watkins S, Whiteside TL (2005) Fas ligand-positive membranous vesicles isolated from sera of patients with oral cancer induce apoptosis of activated T lymphocytes. Clin Cancer Res 11:1010–1020

Kim SH, Bianco N, Menon R, Lechman ER, Shufesky WJ, Morelli AE, Robbins PD (2006) Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol Ther 13:289–300

Kim SH, Bianco NR, Shufesky WJ, Morelli AE, Robbins PD (2007) Effective treatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4. J Immunol 179:2242–2249

Kim SH, Lechman ER, Bianco N, Menon R, Keravala A, Nash J, Mi Z, Watkins SC, Gambotto A, Robbins PD (2005) Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. J Immunol 174:6440–6448

Klibi J, Niki T, Riedel A, Pioche-Durieu C, Souquere S, Rubinstein E, Le Moulec S, Guigay J, Hirashima M, Guemira F, Adhikary D, Mautner J, Busson P (2009) Blood diffusion and Th1-suppressive effects of galectin-9-containing exosomes released by Epstein–Barr virus-infected nasopharyngeal carcinoma cells. Blood 113:1957–1966

Kobayashi T, Startchev K, Whitney AJ, Gruenber J (2001) Localization of lysobisphosphatidic acid-rich membrane domains in late endosomes. Biol Chem 382:483–485

Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T (2010) Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem 285:17442–17452

Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, Salto-Tellez M, Timmers L, Lee CN, El Oakley RM, Pasterkamp G, de Kleijn DP, Lim SK (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4:214–222

Lamparski HG, Metha-Damani A, Yao JY, Patel S, Hsu DH, Ruegg C, Le Pecq JB (2002) Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Meth 270:211–226

Laulagnier K, Motta C, Hamdi S, Roy S, Fauvelle F, Pageaux JF, Kobayashi T, Salles JP, Perret B, Bonnerot C, Record M (2004) Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J 380:161–171

Lenassi M, Cagney G, Liao M, Vaupotic T, Bartholomeeusen K, Cheng Y, Krogan NJ, Plemenitas A, Peterlin BM (2010) HIV Nef is secreted in exosomes and triggers apoptosis in bystander CD4 T cells. Traffic 11:110–122

Liu C, Yu S, Zinn K, Wang J, Zhang L, Jia Y, Kappes JC, Barnes S, Kimberly RP, Grizzle WE, Zhang HG (2006) Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol 176:1375–1385

Liu Y, Xiang X, Zhuang X, Zhang S, Liu C, Cheng Z, Michalek S, Grizzle W, Zhang HG (2010) Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. Am J Pathol 176:290–299

Liu YY, Fan HH, Ren YN, Yang J, Nie XX, Zhao LH, Lin JJ (2008) Immune tolerance induced by exosomes derived from regulatory dendritic cells of mice. Zhongguo Shi Yan Xue Ye Xue Za Zhi 16:406–410

Logozzi M, De Milito A, Lugini L, Borghi M, Calabro L, Spada M, Perdicchio M, Marino ML, Federici C, Iessi E, Brambilla D, Venturi G, Lozupone F, Santinami M, Huber V, Maio M, Rivoltini L, Fais S (2009) High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS ONE 4:e5219

Loomis RJ, Holmes DA, Elms A, Solski PA, Der CJ, Su L (2006) Citron kinase, a RhoA effector, enhances HIV-1 virion production by modulating exocytosis. Traffic 7:1643–1653

Looze C, Yui D, Leung L, Ingham M, Kaler M, Yao X, Wu WW, Shen RF, Daniels MP, Levine SJ (2009) Proteomic profiling of human plasma exosomes identifies PPARgamma as an exosome-associated protein. Biochem Biophys Res Commun 378:433–438

Luketic L, Delanghe J, Sobol PT, Yang P, Frotten E, Mossman KL, Gauldie J, Bramson J, Wan Y (2007) Antigen presentation by exosomes released from peptide-pulsed dendritic cells is not suppressed by the presence of active CTL. J Immunol 179:5024–5032

Mack M, Kleinschmidt A, Bruhl H, Klier C, Nelson PJ, Cihak J, Plachy J, Stangassinger M, Erfle V, Schlondorff D (2000) Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat Med 6:769–775

Mallegol J, Van Niel G, Lebreton C, Lepelletier Y, Candalh C, Dugave C, Heath JK, Raposo G, Cerf-Bensussan N, Heyman M (2007) T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology 132:1866–1876

Masyuk AI, Huang BQ, Ward CJ, Gradilone SA, Banales JM, Masyuk TV, Radtke B, Splinter PL, Larusso NF (2010) Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am J Physiol Gastrointest Liver Physiol 299:G990–G999

Mathivanan S, Simpson RJ (2009) ExoCarta: a compendium of exosomal proteins and RNA. Proteomics 9:4997–5000

Matsuo H, Chevallier J, Mayran N, Le Blanc I, Ferguson C, Faure J, Blanc NS, Matile S, Dubochet J, Sadoul R, Parton RG, Vilbois F, Gruenberg J (2004) Role of LBPA and Alix in multivesicular liposome formation and endosome organization. Science 303:531–534

Menager MM, Menasche G, Romao M, Knapnougel P, Ho CH, Garfa M, Raposo G, Feldmann J, Fischer A, de Saint Basile G (2007) Secretory cytotoxic granule maturation and exocytosis require the effector protein hMunc13-4. Nat Immunol 8:257–267

Miksa M, Wu R, Dong W, Das P, Yang D, Wang P (2006) Dendritic cell-derived exosomes containing milk fat globule epidermal growth factor-factor VIII attenuate proinflammatory responses in sepsis. Shock 25:586–593

Miksa M, Wu R, Dong W, Komura H, Amin D, Ji Y, Wang Z, Wang H, Ravikumar TS, Tracey KJ, Wang P (2009) Immature dendritic cell-derived exosomes rescue septic animals via milk fat globule epidermal growth factor VIII. J Immunol 183:5983–5990

Miranda KC, Bond DT, McKee M, Skog J, Paunescu TG, Da Silva N, Brown D, Russo LM (2010) Nucleic acids within urinary exosomes/microvesicles are potential biomarkers for renal disease. Kidney Int 78:191–199

Mitchell P, Petfalski E, Shevchenko A, Mann M, Tollervey D (1997) The exosome: a conserved eukaryotic RNA processing complex containing multiple 3′– > 5′ exoribonucleases. Cell 91:457–466

Mitchell PJ, Welton J, Staffurth J, Court J, Mason MD, Tabi Z, Clayton A (2009) Can urinary exosomes act as treatment response markers in prostate cancer? J Transl Med 7:4

Miyanishi M, Tada K, Koike M, Uchiyama Y, Kitamura T, Nagata S (2007) Identification of Tim4 as a phosphatidylserine receptor. Nature 450:435–439

Miyasaka K, Hanayama R, Tanaka M, Nagata S (2004) Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells. Eur J Immunol 34:1414–1422

Mizuno K, Tolmachova T, Ushakov DS, Romao M, Abrink M, Ferenczi MA, Raposo G, Seabra MC (2007) Rab27b regulates mast cell granule dynamics and secretion. Traffic 8:883–892

Monleon I, Martinez-Lorenzo MJ, Monteagudo L, Lasierra P, Taules M, Iturralde M, Pineiro A, Larrad L, Alava MA, Naval J, Anel A (2001) 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

Montecalvo A, Shufesky WJ, Stolz DB, Sullivan MG, Wang Z, Divito SJ, Papworth GD, Watkins SC, Robbins PD, Larregina AT, Morelli AE (2008) Exosomes as a short-range mechanism to spread alloantigen between dendritic cells during T cell allorecognition. J Immunol 180:3081–3090

Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB, Papworth GD, Zahorchak AF, Logar AJ, Wang Z, Watkins SC, Falo LD Jr, Thomson AW (2004) Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 104:3257–3266

Morse MA, Garst J, Osada T, Khan S, Hobeika A, Clay TM, Valente N, Shreeniwas R, Sutton MA, Delcayre A, Hsu DH, Le Pecq JB, Lyerly HK (2005) A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J Transl Med 3:9

Muntasell A, Berger AC, Roche PA (2007) T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J 26:4263–4272

Napoletano C, Rughetti A, Landi R, Pinto D, Bellati F, Rahimi H, Spinelli GP, Pauselli S, Sale P, Dolo V, De Lorenzo F, Tomao F, Benedetti-Panici P, Frati L, Nuti M (2009) Immunogenicity of allo-vesicle carrying ERBB2 tumor antigen for dendritic cell-based anti-tumor immunotherapy. Int J Immunopathol Pharmacol 22:647–658

Nazarenko I, Rana S, Baumann A, McAlear J, Hellwig A, Trendelenburg M, Lochnit G, Preissner KT, Zoller M (2010) Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res 70:1668–1678

Nilsson J, Skog J, Nordstrand A, Baranov V, Mincheva-Nilsson L, Breakefield XO, Widmark A (2009) Prostate cancer-derived urine exosomes: a novel approach to biomarkers for prostate cancer. Br J Cancer 100:1603–1607

Nolte-'t Hoen EN, Buschow SI, Anderton SM, Stoorvogel W, Wauben MH (2009) Activated T-cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 113:1977–1981

Oliveira DL, Freire-de-Lima CG, Nosanchuk JD, Casadevall A, Rodrigues ML, Nimrichter L (2010) Extracellular vesicles from cryptococcus neoformans modulate macrophage functions. Infect Immun 78:1601–1609

Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C (2010) Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol 12:19–30

Palanisamy V, Sharma S, Deshpande A, Zhou H, Gimzewski J, Wong DT (2010) Nanostructural and transcriptomic analyses of human saliva derived exosomes. PLoS ONE 5:e8577

Pan BT, Teng K, Wu C, Adam M, Johnstone RM (1985) Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol 101:942–948

Parolini I, Federici C, Raggi C, Lugini L, Palleschi S, de Milito A, Coscia C, Iessi E, Logozzi MA, Molinari A, Colone M, Tatti M, Sargiacomo M, Fais S (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284:34211–34222

Peche H, Heslan M, Usal C, Amigorena S, Cuturi MC (2003) Presentation of donor major histocompatibility complex antigens by bone marrow dendritic cell-derived exosomes modulates allograft rejection. Transplantation 76:1503–1510

Peche H, Renaudin K, Beriou G, Merieau E, Amigorena S, Cuturi MC (2006) Induction of tolerance by exosomes and short-term immunosuppression in a fully MHC-mismatched rat cardiac allograft model. Am J Transplant 6:1541–1550

Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, de Gruijl TD, Wurdinger T, Middeldorp JM (2010) Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci USA 107:6328–6333

Pisitkun T, Shen RF, Knepper MA (2004) Identification and proteomic profiling of exosomes in human urine. Proc Natl Acad Sci USA 101:13368–13373

Poliakov A, Spilman M, Dokland T, Amling CL, Mobley JA (2009) Structural heterogeneity and protein composition of exosome-like vesicles (prostasomes) in human semen. Prostate 69:159–167

Potolicchio I, Carven GJ, Xu X, Stipp C, Riese RJ, Stern LJ, Santambrogio L (2005) Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J Immunol 175:2237–2243

Poutsiaka DD, Schroder EW, Taylor DD, Levy EM, Black PH (1985) Membrane vesicles shed by murine melanoma cells selectively inhibit the expression of Ia antigen by macrophages. J Immunol 134:138–144

Prado N, Canamero M, Villalba M, Rodriguez R, Batanero E (2010) Bystander suppression to unrelated allergen sensitization through intranasal administration of tolerogenic exosomes in mouse. Mol Immunol 47:2148–2151

Prado N, Marazuela EG, Segura E, Fernandez-Garcia H, Villalba M, Thery C, Rodriguez R, Batanero E (2008) Exosomes from bronchoalveolar fluid of tolerized mice prevent allergic reaction. J Immunol 181:1519–1525

Qazi KR, Gehrmann U, Jordo ED, Karlsson MC, Gabrielsson S (2009) Antigen loaded exosomes alone induce Th1 type memory through a B-cell dependent mechanism. Blood 113:2673–2683

Qazi KR, Torregrosa Paredes P, Dahlberg B, Grunewald J, Eklund A, Gabrielsson S (2010) Proinflammatory exosomes in bronchoalveolar lavage fluid of patients with sarcoidosis. Thorax 65(11):1016–1024

Quah BJ, O'Neill HC (2007) Mycoplasma contaminants present in exosome preparations induce polyclonal B cell responses. J Leukoc Biol 82:1070–1082

Rabinowits G, Gercel-Taylor C, Day JM, Taylor DD, Kloecker GH (2009) Exosomal MicroRNA: a diagnostic marker for lung cancer. Clin Lung Cancer 10:42–46

Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, Geuze HJ (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183:1161–1172

Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, Ratajczak MZ (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20:847–856

Rechavi O, Erlich Y, Amram H, Flomenblit L, Karginov FV, Goldstein I, Hannon GJ, Kloog Y (2009) Cell contact-dependent acquisition of cellular and viral nonautonomously encoded small RNAs. Genes Dev 23:1971–1979

Savina A, Furlan M, Vidal M, Colombo MI (2003) Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J Biol Chem 278:20083–20090

Savina A, Vidal M, Colombo MI (2002) The exosome pathway in K562 cells is regulated by Rab11. J Cell Sci 115:2505–2515

Scheinecker C, McHugh R, Shevach EM, Germain RN (2002) Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med 196:1079–1090

Schnitzer JK, Berzel S, Fajardo-Moser M, Remer KA, Moll H (2010) Fragments of antigen-loaded dendritic cells (DC) and DC-derived exosomes induce protective immunity against Leishmania major. Vaccine 28:5785–5793

Segura E, Guerin C, Hogg N, Amigorena S, Thery C (2007) CD8+ dendritic cells use LFA-1 to capture MHC-peptide complexes from exosomes in vivo. J Immunol 179:1489–1496

Segura E, Nicco C, Lombard B, Véron P, Raposo G, Batteux F, Amigorena S, Thery C (2005) ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T cell priming. Blood 106:216–223

Silverman JM, Clos J, De'oliveira CC, Shirvani O, Fang Y, Wang C, Foster LJ, Reiner NE (2010) An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages. J Cell Sci 123:842–852

Silverman JM, Clos J, Horakova E, Wang AY, Wiesgigl M, Kelly I, Lynn MA, McMaster WR, Foster LJ, Levings MK, Reiner NE (2010) Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells. J Immunol 185(9):5011–5022

Simpson RJ, Jensen SS, Lim JW (2008) Proteomic profiling of exosomes: current perspectives. Proteomics 8:4083–4099

Simpson RJ, Lim JW, Moritz RL, Mathivanan S (2009) Exosomes: proteomic insights and diagnostic potential. Expert Rev Proteomics 6:267–283

Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Curry WT Jr, Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476

Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH, Verjee SS, Jones LA, Hershberg RM (2006) Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 24:3089–3094

Stinchcombe JC, Griffiths GM (2007) Secretory mechanisms in cell-mediated cytotoxicity. Annu Rev Cell Dev Biol 23:495–517

Subra C, Laulagnier K, Perret B, Record M (2007) Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 89:205–212

Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL (2010) Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLoS ONE 5:e11469

Taieb J, Chaput N, Schartz N, Roux S, Novault S, Menard C, Ghiringhelli F, Terme M, Carpentier AF, Darrasse-Jeze G, Lemonnier F, Zitvogel L (2006) Chemoimmunotherapy of tumors: cyclophosphamide synergizes with exosome based vaccines. J Immunol 176:2722–2729

Tardif MR, Tremblay MJ (2005) Regulation of LFA-1 activity through cytoskeleton remodeling and signaling components modulates the efficiency of HIV type-1 entry in activated CD4+ T lymphocytes. J Immunol 175:926–935

Taylor DD, Akyol S, Gercel-Taylor C (2006) Pregnancy-associated exosomes and their modulation of T cell signaling. J Immunol 176:1534–1542

Taylor DD, Gercel-Taylor C (2008) MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110:13–21

Taylor DD, Gercel-Taylor C (2005) Tumour-derived exosomes and their role in cancer-associated T-cell signalling defects. Br J Cancer 92:305–311

Taylor DD, Gercel-Taylor C, Lyons KS, Stanson J, Whiteside TL (2003) T-cell apoptosis and suppression of T-cell receptor/CD3-zeta by Fas ligand-containing membrane vesicles shed from ovarian tumors. Clin Cancer Res 9:5113–5119

Taylor MR, Couto JR, Scallan CD, Ceriani RL, Peterson JA (1997) Lactadherin (formerly BA46), a membrane-associated glycoprotein expressed in human milk and breast carcinomas, promotes Arg-Gly-Asp (RGD)-dependent cell adhesion. DNA Cell Biol 16:861–869

Theos AC, Truschel ST, Tenza D, Hurbain I, Harper DC, Berson JF, Thomas PC, Raposo G, Marks MS (2006) A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. Dev Cell 10:343–354

Thery C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol Chapter 3:Unit 3 22

Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, Garin J, Amigorena S (2001) Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol 166:7309–7318

Thery C, Duban L, Segura E, Veron P, Lantz O, Amigorena S (2002) Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol 3:1156–1162

Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9:581–593

Thery C, Regnault A, Garin J, Wolfers J, Zitvogel L, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1999) Molecular characterization of dendritic cell-derived exosomes. Selective accumulation of the heat shock protein hsc73. J Cell Biol 147:599–610

Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, Schwille P, Brugger B, Simons M (2008) Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319:1244–1247

Utsugi-Kobukai S, Fujimaki H, Hotta C, Nakazawa M, Minami M (2003) MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells. Immunol Lett 89:125–131

Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659

Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, Corbelli A, Fais S, Parmiani G, Rivoltini L (2006) Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 66:9290–9298

Van Niel G, Mallegol J, Bevilacqua C, Candalh C, Brugiere S, Tomaskovic-Crook E, Heath JK, Cerf-Bensussan N, Heyman M (2003) Intestinal epithelial exosomes carry MHC class II/peptides able to inform the immune system in mice. Gut 52:1690–1697

van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R, Cerf-Bensussan N, Heyman M (2001) Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology 121:337–349

Vega VL, Rodriguez-Silva M, Frey T, Gehrmann M, Diaz JC, Steinem C, Multhoff G, Arispe N, De Maio A (2008) Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol 180:4299–4307

Veron P, Segura E, Sugano G, Amigorena S, Thery C (2005) Accumulation of MFG-E8/lactadherin on exosomes from immature dendritic cells. Blood Cells Mol Dis 35:81–88

Viaud S, Ploix S, Lapierre V, Thery C, Commere P-H, Tramalloni D, Gorrichon K, Virault-Rocroy P, Tursz T, Lantz O, Zitvogel L, Chaput N (2010) Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of IFNg. J Immunotherapy (in press)

Viaud S, Terme M, Flament C, Taieb J, Andre F, Novault S, Escudier B, Robert C, Caillat-Zucman S, Tursz T, Zitvogel L, Chaput N (2009) Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PLoS ONE 4:e4942

Viaud S, Thery C, Ploix S, Tursz T, Lapierre V, Lantz O, Zitvogel L, Chaput N (2010) Dendritic cell-derived exosomes for cancer immunotherapy: what’s next? Cancer Res 70:1281–1285

Vidal M, Sainte-Marie J, Philippot JR, Bienvenue A (1989) Asymmetric distribution of phospholipids in the membrane of vesicles released during in vitro maturation of guinea pig reticulocytes: evidence precluding a role for “aminophospholipid translocase”. J Cell Physiol 140:455–462

Walker JD, Maier CL, Pober JS (2009) Cytomegalovirus-infected human endothelial cells can stimulate allogeneic CD4+ memory T cells by releasing antigenic exosomes. J Immunol 182:1548–1559

Wang GJ, Liu Y, Qin A, Shah SV, Deng ZB, Xiang X, Cheng Z, Liu C, Wang J, Zhang L, Grizzle WE, Zhang HG (2008) Thymus exosomes-like particles induce regulatory T cells. J Immunol 181:5242–5248

Wieckowski EU, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ, Whiteside TL (2009) Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. J Immunol 183:3720–3730

Wolfers J, Lozier A, Raposo G, Regnault A, Thery C, Masurier C, Flament C, Pouzieux S, Faure F, Tursz T, Angevin E, Amigorena S, Zitvogel L (2001) Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming. Nat Med 7:297–303

Wubbolts R, Leckie RS, Veenhuizen PT, Schwarzmann G, Mobius W, Hoernschemeyer J, Slot JW, Geuze HJ, Stoorvogel W (2003) Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation. J Biol Chem 278:10963–10972

Xiang X, Liu Y, Zhuang X, Zhang S, Michalek S, Taylor DD, Grizzle W, Zhang HG (2010) TLR2-mediated expansion of MDSCs is dependent on the source of tumor exosomes. Am J Pathol 177:1606–1610

Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, Cheng Z, Shah SV, Wang GJ, Zhang L, Grizzle WE, Mobley J, Zhang HG (2009) Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer 124:2621–2633

Yang X, Meng S, Jiang H, Chen T, Wu W (2010) Exosomes derived from interleukin-10-treated dendritic cells can inhibit trinitrobenzene sulfonic acid-induced rat colitis. Scand J Gastroenterol 45:1168–1177

Yu S, Liu C, Su K, Wang J, Liu Y, Zhang L, Li C, Cong Y, Kimberly R, Grizzle WE, Falkson C, Zhang HG (2007) Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol 178:6867–6875

Zeelenberg IS, Ostrowski M, Krumeich S, Bobrie A, Jancic C, Boissonnas A, Delcayre A, Le Pecq JB, Combadiere B, Amigorena S, Thery C (2008) Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses. Cancer Res 68:1228–1235

Zhang HG, Liu C, Su K, Yu S, Zhang L, Zhang S, Wang J, Cao X, Grizzle W, Kimberly RP (2006) A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death. J Immunol 176:7385–7393

Zhang Y, Liu D, Chen X, Li J, Li L, Bian Z, Sun F, Lu J, Yin Y, Cai X, Sun Q, Wang K, Ba Y, Wang Q, Wang D, Yang J, Liu P, Xu T, Yan Q, Zhang J, Zen K, Zhang CY (2010) Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 39:133–144

Zhou H, Yuen PS, Pisitkun T, Gonzales PA, Yasuda H, Dear JW, Gross P, Knepper MA, Star RA (2006) Collection, storage, preservation, and normalization of human urinary exosomes for biomarker discovery. Kidney Int 69:1471–1476

Zitvogel L, Regnault A, Lozier A, Wolfers J, Flament C, Tenza D, Ricciardi-Castagnoli P, Raposo G, Amigorena S (1998) Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 4:594–600