Exosomes: Mediators of Immune Regulation

Document Type : Review article


1 Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

2 Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.


Extracellular Vesicles, including exosomes, are small membrane fragments released from many cell types, like Mesenchymal Stem Cells (MSCs). They were recognized as a mechanism of intercellular communication. They can transfer proteins, lipids and nucleic acids to other cells. Thus, they have many physiological (angiogenesis, coagulation and tissue repair, etc.) and pathological (e.g. in autoimmune diseases and cancer) effects. The immunomodulatory properties of them have drawn a lot of interest. In particular, MSC-derived exosomes seem to have therapeutic potentials for many diseases. We reviewed the biopathological effects of exosomes and their roles in modulating immune responses.


van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of Extracellular Vesicles. Nature Reviews Molecular Cell Biology. 2018; 19(4):213-28. [DOI:10.1038/nrm.2017.125] [PMID]
Andaloussi SE, Mager I, Breakefield XO, Wood MJ. Extracellular Vesicles: Biology and emerging therapeutic opportunities. Nature Reviews Drug Discovery. 2013; 12(5):347-57. [DOI:10.1038/nrd3978] [PMID]
Yanez Mo M, Siljander PR, Andreu Z, Zavec AB, Borras FE, Buzas EI, et al. Biological properties of Extracellular Vesicles and their physiological functions. Journal of Extracellular Vesicles. 2015; 4(1):27066. [DOI:10.3402/jev.v4.27066] [PMID] [PMCID]
Tetta C, Bruno S, Fonsato V, Deregibus MC, Camussi G. The role of microvesicles in tissue repair. Organogenesis. 2011; 7(2):105-15. [DOI:10.4161/org.7.2.15782] [PMID] [PMCID]
Chargaff E, West R. The biological significance of the thromboplastic protein of blood. The Journal of Biological Chemistry. 1946; 166(1):189-97. [PMID]
Wolf P. The nature and significance of platelet products in human plasma. British Journal of Haematology. 1967; 13(3):269-88. [DOI:10.1111/j.1365-2141.1967.tb08741.x] [PMID]
Pan BT, Teng K, Wu C, Adam M, Johnstone RM. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. The Journal of Cell Biology. 1985; 101(3):942-8. [DOI:10.1083/jcb.101.3.942] [PMID]
Raiborg C, Stenmark H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature. 2009; 458(7237):445-52. [DOI:10.1038/nature07961] [PMID]
Riazifar M, Pone EJ, Lotvall J, Zhao W. Stem cell Extracellular Vesicles: Extended messages of regeneration. Annual Review of Pharmacology and Toxicology. 2017; 57:125-54. [DOI:10.1146/annurev-pharmtox-061616-030146] [PMID] [PMCID]
Zhang W, Jiang X, Bao J, Wang Y, Liu H, Tang L. Exosomes in pathogen infections: A bridge to deliver molecules and link functions. Frontiers in Immunology. 2018; 9:90. [DOI:10.3389/fimmu.2018.00090] [PMID] [PMCID]
Stremersch S, De Smedt SC, Raemdonck K. Therapeutic and diagnostic applications of Extracellular Vesicles. Journal of Controlled Release. 2016; 244(Pt B):167-83.
van der Pol E, Boing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of Extracellular Vesicles. Pharmacological Reviews. 2012; 64(3):676-705. [DOI:10.1124/pr.112.005983] [PMID]
Raposo G, Stoorvogel W. Extracellular Vesicles: Exosomes, microvesicles, and friends. The Journal of Cell Biology. 2013; 200(4):373-83. [DOI:10.1083/jcb.201211138] [PMID] [PMCID]
Berckmans RJ, Sturk A, van Tienen LM, Schaap MC, Nieuwland R. Cell-derived vesicles exposing coagulant tissue factor in saliva. Blood. 2011; 117(11):3172-80. [DOI:10.1182/blood-2010-06-290460] [PMID]
Yin W, Ouyang S, Li Y, Xiao B, Yang H. Immature dendritic cell-derived exosomes: A promise subcellular vaccine for autoimmunity. Inflammation. 2013; 36(1):232-40. [DOI:10.1007/s10753-012-9539-1] [PMID]
Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, et al. A novel nanoparticle drug delivery system: The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molecular Therapy. 2010; 18(9):1606-14. [DOI:10.1038/mt.2010.105] [PMID] [PMCID]
Yeung CLA, Co NN, Tsuruga T, Yeung TL, Kwan SY, Leung CS, et al. Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1. Nature Communications. 2016; 7:11150. [DOI:10.1038/ncomms11150] [PMID] [PMCID]
Bellingham SA, Guo BB, Coleman BM, Hill AF. Exosomes: Vehicles for the transfer of toxic proteins associated with neurodegenerative diseases. Frontiers in Physiology. 2012; 3:124. [DOI:10.3389/fphys.2012.00124] [PMID] [PMCID]
Mack M, Kleinschmidt A, Brühl H, Klier C, Nelson PJ, Cihak J, et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: A mechanism for cellular human immunodeficiency virus 1 infection. Nature Medicine. 2000; 6(7):769-75. [DOI:10.1038/77498] [PMID]
Chaput N, Thery C. Exosomes: Immune properties and potential clinical implementations. Seminars in Immunopathology. 2011; 33(5):419-40. [DOI:10.1007/s00281-010-0233-9] [PMID]
Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nature Reviews Immunology. 2009; 9(8):581-93. [DOI:10.1038/nri2567] [PMID]
Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, Melief CJ, et al. B lymphocytes secrete antigen-presenting vesicles. The Journal of Experimental Medicine. 1996; 183(3):1161-72. [DOI:10.1084/jem.183.3.1161] [PMID]
Segura E, Nicco C, Lombard B, Veron P, Raposo G, Batteux F, et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood. 2005; 106(1):216-23. [DOI:10.1182/blood-2005-01-0220] [PMID]
Peche H, Heslan M, Usal C, Amigorena S, Cuturi MC. Presentation of donor major histocompatibility complex antigens by bone marrow dendritic cell-derived exosomes modulates allograft rejection. Transplantation. 2003; 76(10):1503-10. [DOI:10.1097/01.TP.0000092494.75313.38] [PMID]
Thery C, Duban L, Segura E, Veron P, Lantz O, Amigorena S. Indirect activation of naive CD4+ T cells by dendritic cell-derived exosomes. Nature Immunology. 2002; 3(12):1156-62. [DOI:10.1038/ni854] [PMID]
Bhatnagar S, Schorey JS. Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. The Journal of Biological Chemistry. 2007; 282(35):25779-89. [DOI:10.1074/jbc.M702277200] [PMID] [PMCID]
Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Research. 2005; 65(12):5238-47. [DOI:10.1158/0008-5472.CAN-04-3804] [PMID] [PMCID]
Vega VL, Rodriguez Silva M, Frey T, Gehrmann M, Diaz JC, Steinem C, et al. Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. Journal of Immunology. 2008; 180(6):4299-307. [DOI:10.4049/jimmunol.180.6.4299] [PMID]
Poutsiaka DD, Schroder EW, Taylor DD, Levy EM, Black PH. Membrane vesicles shed by murine melanoma cells selectively inhibit the expression of Ia antigen by macrophages. Journal of Immunology. 1985; 134(1):138-44. [PMID]
Klibi J, Niki T, Riedel A, Pioche Durieu C, Souquere S, Rubinstein E, et al. Blood diffusion and Th1-suppressive effects of galectin-9–containing exosomes released by Epstein-Barr virus-infected nasopharyngeal carcinoma cells. Blood. 2009; 113(9):1957-66. [DOI:10.1182/blood-2008-02-142596] [PMID]
Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, et al. Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles. The Journal of Experimental Medicine. 2002; 195(10):1303-16. [DOI:10.1084/jem.20011624] [PMID] [PMCID]
Czystowska M, Han J, Szczepanski MJ, Szajnik M, Quadrini K, Brandwein H, et al. IRX-2, a novel immunotherapeutic, protects human T cells from tumor-induced cell death. Cell Death and Differentiation. 2009; 16(5):708-18. [DOI:10.1038/cdd.2008.197] [PMID] [PMCID]
Huber V, Fais S, Iero M, Lugini L, Canese P, Squarcina P, et al. Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: Role in immune escape. Gastroenterology. 2005; 128(7):1796-804. [DOI:10.1053/j.gastro.2005.03.045] [PMID]
Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z. Human tumor-derived exosomes selectively impair lymphocyte responses to Interleukin-2. Cancer Research. 2007; 67(15):7458-66. [DOI:10.1158/0008-5472.CAN-06-3456] [PMID]
Szajnik M, Czystowska M, Szczepanski MJ, Mandapathil M, Whiteside TL. Tumor-derived microvesicles induce, expand and up-regulate biological activities of human regulatory T cells (Treg). PLOS One. 2010; 5(7):e11469. [DOI:10.1371/journal.pone.0011469] [PMID] [PMCID]
Wieckowski EU, Visus C, Szajnik M, Szczepanski MJ, Storkus WJ, Whiteside TL. Tumor-derived microvesicles promote regulatory T cell expansion and induce apoptosis in tumor-reactive activated CD8+ T lymphocytes. Journal of Immunology. 2009; 183(6):3720-30. [DOI:10.4049/jimmunol.0900970] [PMID] [PMCID]
Liu C, Yu S, Zinn K, Wang J, Zhang L, Jia Y, et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. Journal of Immunology. 2006; 176(3):1375-85. [DOI:10.4049/jimmunol.176.3.1375] [PMID]
Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z. Human tumor-derived exosomes down-modulate NKG2D expression. Journal of Immunology. 2008; 180(11):7249-58. [DOI:10.4049/jimmunol.180.11.7249] [PMID]
Ashiru O, Boutet P, Fernandez Messina L, Aguera Gonzalez S, Skepper JN, Vales Gomez M, et al. Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes. Cancer Research. 2010; 70(2):481-9. [DOI:10.1158/0008-5472.CAN-09-1688] [PMID] [PMCID]
Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy Martin JP, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. The Journal of Clinical Investigation. 2010; 120(2):457-71. [DOI:10.1172/JCI40483]
Liu Y, Xiang X, Zhuang X, Zhang S, Liu C, Cheng Z, et al. Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells. The American Journal of Pathology. 2010; 176(5):2490-9. [DOI:10.2353/ajpath.2010.090777] [PMID] [PMCID]
Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, Villa A, et al. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Research. 2006; 66(18):9290-8. [DOI:10.1158/0008-5472.CAN-06-1819] [PMID]
Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, et al. Induction of myeloid-derived suppressor cells by tumor exosomes. International Journal of Cancer. 2009; 124(11):2621-33. [DOI:10.1002/ijc.24249] [PMID] [PMCID]
Yu S, Liu C, Su K, Wang J, Liu Y, Zhang L, et al. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. Journal of Immunology. 2007; 178(11):6867-75. [DOI:10.4049/jimmunol.178.11.6867] [PMID]
Taylor DD, Akyol S, Gercel Taylor C. Pregnancy-associated exosomes and their modulation of T cell signaling. Journal of Immunology. 2006; 176(3):1534-42. [DOI:10.4049/jimmunol.176.3.1534] [PMID]
Lenassi M, Cagney G, Liao M, Vaupotic T, Bartholomeeusen K, Cheng Y, et al. HIV Nef is secreted in exosomes and triggers apoptosis in bystander CD4+ T cells. Traffic. 2010; 11(1):110-22. [DOI:10.1111/j.1600-0854.2009.01006.x] [PMID] [PMCID]
Bruno S, Deregibus MC, Camussi G. The secretome of mesenchymal stromal cells: Role of Extracellular Vesicles in immunomodulation. Immunology Letters. 2015; 168(2):154-8. [DOI:10.1016/j.imlet.2015.06.007] [PMID]
Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney International. 2010; 78(9):838-48. [DOI:10.1038/ki.2010.278] [PMID]
Eirin A, Riester SM, Zhu XY, Tang H, Evans JM, O’Brien D, et al. MicroRNA and mRNA cargo of Extracellular Vesicles from porcine adipose tissue-derived Mesenchymal Stem Cells. Gene. 2014; 551(1):55-64. [DOI:10.1016/j.gene.2014.08.041] [PMID] [PMCID]
Burrello J, Monticone S, Gai C, Gomez Y, Kholia S, Camussi G. Stem cell-derived Extracellular Vesicles and immune-modulation. Frontiers in Cell and Developmental Biology. 2016; 4:83. [DOI:10.3389/fcell.2016.00083] [PMID] [PMCID]
Alcayaga-Miranda F, Varas-Godoy M, Khoury M. Harnessing the angiogenic potential of stem cell-derived exosomes for vascular regeneration. Stem Cells International. 2016; 2016:3409169. [DOI:10.1155/2016/3409169] [PMID] [PMCID]
Blazquez R, Sanchez Margallo FM, de la Rosa O, Dalemans W, Alvarez V, Tarazona R, et al. Immunomodulatory potential of human adipose Mesenchymal Stem Cells derived exosomes on in vitro stimulated T cells. Frontiers in Immunology. 2014; 5:556. [DOI:10.3389/fimmu.2014.00556] [PMID] [PMCID]
Amarnath S, Foley JE, Farthing DE, Gress RE, Laurence A, Eckhaus MA, et al. Bone marrow-derived mesenchymal stromal cells harness purinergenic signaling to tolerize human Th1 cells in vivo. Stem Cells. 2015; 33(4):1200-12. [DOI:10.1002/stem.1934] [PMID] [PMCID]
Del Fattore A, Luciano R, Saracino R, Battafarano G, Rizzo C, Pascucci L, et al. Differential effects of Extracellular Vesicles secreted by Mesenchymal Stem Cells from different sources on glioblastoma cells. Expert Opinion on Biological Therapy. 2015; 15(4):495-504. [DOI:10.1517/14712598.2015.997706] [PMID]
Di Trapani M, Bassi G, Midolo M, Gatti A, Kamga PT, Cassaro A, et al. Differential and transferable modulatory effects of mesenchymal stromal cell-derived Extracellular Vesicles on T, B and NK cell functions. Scientific Reports. 2016; 6:24120. [DOI:10.1038/srep24120] [PMID] [PMCID]
Mokarizadeh A, Delirezh N, Morshedi A, Mosayebi G, Farshid AA, Dalir Naghadeh B. Phenotypic modulation of auto-reactive cells by insertion of tolerogenic molecules via MSC-derived exosomes. Veterinary Research Forum. 2012; 3(4):257-61. [PMID] [PMCID]
Favaro E, Carpanetto A, Lamorte S, Fusco A, Caorsi C, Deregibus MC, et al. Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes. Diabetologia. 2014; 57(8):1664-73. [DOI:10.1007/s00125-014-3262-4] [PMID]