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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3257-3266. Prepublished online as a Blood First Edition Paper on July 29, 2004; DOI 10.1182/blood-2004-03-0824. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-0824v1 104/10/3257    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Morelli, A. E. Articles by Thomson, A. W. Search for Related Content PubMed PubMed Citation Articles by Morelli, A. E. Articles by Thomson, A. W. Related Collections Immunobiology Phagocytes Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells Adrian E. Morelli, Adriana T. Larregina, William J. Shufesky, Mara L. G. Sullivan, Donna Beer Stolz, Glenn D. Papworth, Alan F. Zahorchak, Alison J. Logar, Zhiliang Wang, Simon C. Watkins, Louis D. Falo, Jr, and Angus W. Thomson From the Thomas E. Starzl Transplantation Institute; the Department of Surgery and the Department of Dermatology, University of Pittsburgh Cancer Institute; the Department of Immunology and the Department of Cell Biology; and the Physiology and Center for Biologic Imaging, University of Pittsburgh Medical Center, Pittsburgh, PA. Exosomes are nanovesicles released by leukocytes and epithelial cells. Although their function remains enigmatic, exosomes are a source of antigen and transfer functional major histocompatibility complex (MHC)–I/peptide complexes to dendritic cells (DCs) for CD8+ T-cell activation. Here we demonstrate that exosomes also are internalized and processed by immature DCs for presentation to CD4+ T cells. Endocytosed exosomes are sorted into the endocytic compartment of DCs for processing, followed by loading of exosome-derived peptides in MHC-II molecules for presentation to CD4+ T cells. Targeting of exosomes to DCs is mediated via milk fat globule (MFG)–E8/lactadherin, CD11a, CD54, phosphatidylserine, and the tetraspanins CD9 and CD81 on the exosome and v/3 integrin, and CD11a and CD54 on the DCs. Circulating exosomes are internalized by DCs and specialized phagocytes of the spleen and by hepatic Kupffer cells. Internalization of blood-borne allogeneic exosomes by splenic DCs does not affect DC maturation and is followed by loading of the exosome-derived allopeptide IE52-68 in IAb by host CD8+ DCs for presentation to CD4+ T cells. These data imply that exosomes present in circulation or extracellular fluids constitute an alternative source of self- or allopeptides for DCs during maintenance of peripheral tolerance or initiation of the indirect pathway of allorecognition in transplantation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Tumne, V. S. Prasad, Y. Chen, D. B. Stolz, K. Saha, D. M. Ratner, M. Ding, S. C. Watkins, and P. Gupta Noncytotoxic Suppression of Human Immunodeficiency Virus Type 1 Transcription by Exosomes Secreted from CD8+ T Cells J. Virol., May 1, 2009; 83(9): 4354 - 4364. [Abstract] [Full Text] [PDF] Y. Qu, L. Ramachandra, S. Mohr, L. Franchi, C. V. Harding, G. Nunez, and G. R. 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