首页 › 研究 › 免疫 › 【大牛综述】Annu Rev Immunol（IF= 28.396）：抗原呈递细胞胞外膜泡（EVs）的抗原呈递作用

【大牛综述】Annu Rev Immunol（IF= 28.396）：抗原呈递细胞胞外膜泡（EVs）的抗原呈递作用

免疫,研究 2018-02-06 21:42  来源： 【大牛综述】Annu Rev Immunol（IF= 28.396）：抗原呈递细胞胞外膜泡（EVs）的抗原呈递作用已关闭评论 5739

 

适应性免疫的启动和维持需要不同类型的免疫细胞之间的多方面交流模式（包括细胞间直接接触、分泌可溶性信号分子和细胞外囊泡[EVs]）。EVs包含直接从质膜出芽的微泡和多囊泡内体分泌的外泌体。膜受体将EVs引导至特定的靶细胞，从而允许定向转移特定和复杂的信号。大多数（即使不是全部）免疫细胞释放EVs。根据其来源细胞的类型和状态，EVs可以促进适应性免疫应答的启动、增大、维持或沉默。这篇综述重点关注专业抗原呈递细胞的EVs，及其已报道的和推测的作用，以及它们的癌症免疫治疗的潜力。

该综述为外泌体领域大牛Willem Stoorvogel所著，参考文献169篇。做外泌体的，尤其是做免疫领域外泌体的小伙伴们一定要关注这篇文献。

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树突状细胞通过EVs与T细胞的交流

当单独的先天免疫力不足以消除入侵的病原体或根除病原体感染或肿瘤细胞时就需要适应性免疫。但与此同时，应该容忍健康的细胞、共生细菌和其他无害环境化合物。好与坏之间的区分需要在抗原测定中具有高水平的选择性，这是由不同免疫细胞之间不同层次的交流决定的。

通讯机制包括直接的细胞间接触，例如抗原呈递细胞（APC）和T细胞之间免疫突触的形成。在免疫突触内，载有肽抗原（pMHC）的主要组织相容性复合物（MHC）分子可以结合同源抗原特异性T细胞受体（TCR）。根据共刺激性膜蛋白和细胞因子的局部可用性，抗原特异性pMHC-TCR相互作用可以随后刺激或抑制T细胞增殖和分化。通过树突细胞（DC）、B细胞、T细胞和在适应性免疫系统内发挥功能的其他细胞类型释放的细胞外囊泡（EV）提供了一种新的甚至更复杂的免疫调节模式。大多数细胞类型均可分泌EVs，并且根据它们的起源显示出许多功能。首先，1996年有报道，人类B细胞来源的EVs可以在体外有效地将MHC II类（MHC-II）肽复合物（pMHC-II）呈递给CD4 T细胞。后来，Thery及其同事发现用含有pMHC-II的EVs注射小鼠也能诱导体内作用，导致抗原特异性幼稚CD4 T细胞的活化。Zitvogel及其同事证明，小鼠骨髓衍生的DC分泌携带MHC-I、MHC-II和T细胞共刺激分子的EVs。当来自培养的DC的EVs上的MHC-I分子装载有肿瘤特异性肽时，它们可以启动肿瘤特异性细胞毒性T淋巴细胞（CTL）并抑制体内肿瘤生长。这三项具有里程碑意义的研究共同为许多研究人员研究EVs在免疫治疗中的作用和可能的应用奠定了基础。免疫细胞的EVs中选择性RNA集合（包括miRNA）的发现进一步增强了EVs在适应性免疫中有复杂功能的实现。然而，应该注意的是，许多在细胞外发现的miRNA并没有被纳入EVs，并且可能只有EVs的一个有限的类别含有生物学上丰富的miRNA。在过去的二十年里，在一些最初的怀疑之后，人们越来越认识到EVs不仅在抗原呈递方面发挥作用，而且在免疫细胞之间的其他交流水平上发挥作用，如关于该主题的发表的研究文章超过1000篇。尽管EVs在抗原呈递方面的重要性已经得到普遍认可，EVs抗原呈递的一些机制方面已经被报道，但EVs的许多调节功能及其在适应性免疫中的独特作用仍有待解决。

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B细胞外泌体功能的假说模式图

EVs包含至少两类：直接从质膜出芽的微泡和由多囊泡内体（MVEs）与质膜融合而分泌的外泌体。外泌体的直径为30-150 nm，平均比微泡（100 nm至>1μm）小，但是它们尺寸分布的重叠和区分性分子标记的缺乏阻碍了将EV分离纯化为某一类别。此外，驱动EVs形成或掺入其内容物的精确分子机制尚未完全解决。因此，关于外泌体和微泡的独特生理作用的研究由于分子干预方法的有限而受到阻碍。尽管如此，近年来该领域还是取得了很大的进展。在这篇综述中，我们使用术语EV，除非特地说明微囊或外泌体。该综述的目的不是广泛地评估目前关于分子分选到EV或EV释放的通用机制的知识，因为这些已经在其他地方进行了综述。基于前人做出的其它高质量的综述，该综述重点关注EVs在专业APCs抗原呈递方面的作用，以及讨论从DCs中分离出来的EVs在癌症免疫治疗方面的潜力。

参考文献：

Lindenbergh MFS, Stoorvogel W. Antigen Presentation by Extracellular Vesicles from Professional Antigen-Presenting Cells. Annu Rev Immunol. 2018 Jan 31. doi: 10.1146/annurev-immunol-041015-055700. [Epub ahead of print] IF= 28.396

通讯作者介绍：

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Prof. dr. W. (Willem) Stoorvogel, 荷兰乌得勒支大学教授，不仅是外泌体领域大牛（可以说与Thery齐名啦，也常有与Thery合作的文章），也是免疫领域的大牛。发表过超级多的、重要的外泌体paper。列举给大家：

  1. O'Driscoll, Lorraine, Stoorvogel, Willem, Théry, Clotilde, Buzas, Edit, Nazarenko, Irina, Siljander, Pia, Yáñez-Mó, María, Fais, Stefano, Giebel, Bernd & Yliperttula, Marjo (15-02-2017). European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD). European Journal of Pharmaceutical Sciences, 98, (pp. 1-3) (3 p.).
  2. Yáñez-Mó, María, Siljander, Pia R-M, Andreu, Zoraida, Zavec, Apolonija Bedina, Borràs, Francesc E, Buzas, Edit I, Buzas, Krisztina, Casal, Enriqueta, Cappello, Francesco, Carvalho, Joana, Colás, Eva, Cordeiro-da Silva, Anabela, Fais, Stefano, Falcon-Perez, Juan M, Ghobrial, Irene M, Giebel, Bernd, Gimona, Mario, Graner, Michael, Gursel, Ihsan, Gursel, Mayda, Heegaard, Niels H H, Hendrix, An, Kierulf, Peter, Kokubun, Katsutoshi, Kosanovic, Maja, Kralj-Iglic, Veronika, Krämer-Albers, Eva-Maria, Laitinen, Saara, Lässer, Cecilia, Lener, Thomas, Ligeti, Erzsébet, Linē, Aija, Lipps, Georg, Llorente, Alicia, Lötvall, Jan, Manček-Keber, Mateja, Marcilla, Antonio, Mittelbrunn, Maria, Nazarenko, Irina, Nolte-'t Hoen, Esther N M, Nyman, Tuula A, O'Driscoll, Lorraine, Olivan, Mireia, Oliveira, Carla, Pállinger, Éva, Del Portillo, Hernando A, Reventós, Jaume, Rigau, Marina, Rohde, Eva, Sammar, Marei, Sánchez-Madrid, Francisco, Santarém, N, Schallmoser, Katharina, Ostenfeld, Marie Stampe, Stoorvogel, Willem, Stukelj, Roman, Van der Grein, Susanne G, Vasconcelos, M Helena, Wauben, Marca H M & De Wever, Olivier (2015). Biological properties of extracellular vesicles and their physiological functions. Journal of Extracellular Vesicles, 4, (pp. 27066). 这篇文章作者超级多，综述得超级全面！
  3. Stoorvogel, Willem (2015). Resolving sorting mechanisms into exosomes. Cell Research 国产高分杂志上也有这位大牛发表的文章。
  4. Nolte-'t Hoen, E.N.M., van der Vlist, E.J., de Boer-Brouwer, M., Arkesteijn, G., Stoorvogel, W. & Wauben, M.H.M. (2013). Dynamics of dendritic cell-derived vesicles: high-resolution flow cytometric analysis of extracellular vesicle quantity and quality. Journal of Leukocyte Biology, 93, (pp. 395-402) (8 p.).
  5. van Balkom, B.W.M., de Jong, O.G., Smits, M., Brummelman, J., den Ouden, K., de Bree, P.M., van Eijndhoven, M.A.J., Pegtel, DM, Stoorvogel, W., Wurdinger, W & Verhaar, M.C. (2013). Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood, 121 (19), (pp. 3997-4006) (10 p.).
  6. Raposo, G. & Stoorvogel, W. (2013). Extracellular vesicles: Exosomes, microvesicles, and friends. Journal of Cell Biology, 200 ((4)), (pp. 373-383) (10 p.). 这篇综述很经典。
  7. Aalberts, M., Stout, T.A.E. & Stoorvogel, W. (2013). Prostasomes: extracellular vesicles from the prostate. Reproduction, nov 16 (147), (pp. 1-14) (14 p.).
  8. van der Vlist, E.J., Arkesteijn, G., van de Lest, C.H.A., Stoorvogel, W., Nolte-'t Hoen, E.N.M. & Wauben, M.H.M. (2012). CD4+ T cell activation promotes the differential release of distinct populations of nanosized vesicles. Journal of Extracellular Vesicles
  9. Nolte-'t Hoen, E.N.M., Buermans, H.P., Waasdorp, M., Stoorvogel, W., Wauben, M.H.M. & `t Hoen, P.A.C. (2012). Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. Nucleic Acids Research, 40 (18), (pp. 9272-9285) (14 p.).
  10. van der Vlist, E.J., Nolte-'t Hoen, E.N.M., Stoorvogel, W., Arkesteijn, G. & Wauben, M.H.M. (2012). Fluorescent labeling of nano-sized vesicles released by cells and subsequent quantitative and qualitative analysis by high-resolution flow cytometry. Nature Protocols, Jun 14;7 (7), (pp. 1311-1326) (17 p.).
  11. Stoorvogel, W. (2012). Functional transfer of microRNA by exosomes. Blood, Jan 19 (119 (3)), (pp. 646-648) (3 p.).
  12. Nolte - t Hoen, Esther N M, van der Vlist, Els J., Aalberts, Marian, Mertens, Hendrik C H, Bosch, Berend Jan, Bartelink, Willem, Mastrobattista, Enrico, van Gaal, Ethlinn V B, Stoorvogel, Willem, Arkesteijn, Ger J.A. Arkesteijn & Wauben, Marca H M (2012). Quantitative and qualitative flow cytometric analysis of nanosized cell-derived membrane vesicles. Nanomedicine: Nanotechnology, Biology, and Medicine, 8 (5), (pp. 712-720) (9 p.).
  13. Kalra, H., Simpson, R.J., Ji, H., Aikawa, E., Altevogt, P., Askenase, P., Bond, V.C., Borras, F.E., Breakefield, X., Budnik, V., Buzas, E., Camussi, G., Clayton, A., Cocucci, E., Falcon-Perez, J.M., Gabrielsson, S., Gho, Y.S., Gupta, D., Harsha, H.C., Hendrix, A., Hill, A.F., Inal, J.M., Jenster, G., Kramer-Albers, E.M., Lim, S.K., Llorente, A., Lotvall, J., Marcilla, A., Mincheva-Nilsson, L., Nazarenko, I., Nieuwland, R., Nolte-'t Hoen, E.N.M., Pandey, A, Patel, T., Piper, M.G., Pluchino, S., Prasad, T.S., Rajendran, L., Raposo, G., Record, M., Reid, G.E., Sanchez-Madrid, F., Schiffelers, R.M., Siljander, P., Stensballe, A., Stoorvogel, W., Taylor, D., Thery, C., Valadi, H., van Balkom, B.W.M., Vazquez, J., Vidal, M., Wauben, M.H.M., Yanez-Mo, M., Zoeller, M. & Mathivanan, S. (2012). Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biology, 10 (12), (pp. 10.1371/ journal.pbio.1001450) (1 p.).
  14. Buschow, S.I., van Balkom, B.W.M., Aalberts, M., Heck, A.J.R., Wauben, M.H.M. & Stoorvogel, W. (2010). MHC class II-associated proteins in B-cells exosomes and potential functional implications for exosome biogenesis. Immunology and Cell Biology, 88 (8), (pp. 851-856) (6 p.).
  15. Nolte-'t Hoen, E.N.M., Buschow, S.I., Anderton, S.M., Stoorvogel, W. & Wauben, M.H.M. (2009). Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood, 113 (9), (pp. 1977-1981) (5 p.).
  16. Buschow, S.I., Nolte-'t Hoen, E.N.M., van Niel, G., Pols, M.S., ten Broeke, A.G., Lauwen, M., Ossendorp, F., Melief, C.J.M., Raposo, G., Wubbolts, R.W., Wauben, M.H.M. & Stoorvogel, W. (2009). MHC II in dendritic cells is targeted to lysosomes or T Cell-Induced exosomes via distinct multivesicular body pathways. Traffic, 10, (pp. 1528-1542) (15 p.).
  17. Buschow, S.I., Liefhebber, J.M., Wubbolts, R.W. & Stoorvogel, W. (2005). Exosomes contain ubiquitinated proteins. Blood Cells, Molecules, and Diseases, 35, (pp. 398-403) (5 p.).
  18. Wubbolts, Richard, Leckie, Rachel S, Veenhuizen, Peter T M, Schwarzmann, Guenter, Möbius, Wiebke, Hoernschemeyer, Joerg, Slot, Jan-Willem, Geuze, Hans J & Stoorvogel, Willem (2003). Proteomic and biochemical analyses of human B cell-derived exosomes. Potential implications for their function and multivesicular body formation. Journal of Biological Chemistry, 278 (13), (pp. 10963-72) (10 p.).
  19. Stoorvogel, Willem, Kleijmeer, Monique J, Geuze, Hans J & Raposo, Graça (2002). The biogenesis and functions of exosomes. Traffic, 3 (5), (pp. 321-30) (10 p.).
  20. Martin, S., Ramm, G., Lyttle, C.T., Meerloo, T., Stoorvogel, W. & James, D.E. (2000). Biogenesis of insulin-responsive GLUT4 vesicles is independent of brefeldin A-sensitive trafficking. Traffic, 1, (pp. 652-660) (9 p.).
  21. Denzer, K, Kleijmeer, M J, Heijnen, H F, Stoorvogel, W & Geuze, H J (2000). Exosome - from internal vesicle of the multivesicular body to intercellular signaling device. Journal of Cell Science, 113 Pt 19, (pp. 3365-74) (10 p.).
  22. Ramm, G, Slot, J W, James, D E & Stoorvogel, W (2000). Insulin recruits GLUT4 from specialized VAMP2-carrying vesicles as well as from the dynamic endosomal/trans-Golgi network in rat adipocytes. Molecular Biology of the Cell, 11 (12), (pp. 4079-91) (13 p.).
  23. Escola, J.-M., Kleijmeer, M.J., Stoorvogel, W., Griffith, J.M., Yoshie, O. & Geuze, H.J. (1998). Selective enrichment of tetraspan proteins on the internal vesicles of multivesicular endosomes and on exosomes secreted by human B-lymphocytes. Journal of Biological Chemistry, 32, (pp. 20121-20127) (7 p.).

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