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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-06-1769. This Article Full Text (PDF) All Versions of this Article: 2002-06-1769v1 101/2/611    most recent Alert me when this article is cited Alert me if a correction is posted 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 Social Bookmarking                   What's this? Submitted June 14, 2002 Accepted August 23, 2002 Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production Adrian E Morelli*, Adriana T Larregina, William J Shufesky, Alan F Zahorchack, Alison J Logar, Glenn D Papworth, Zhiliang Wang, Simon C Watkins, Louis D Falo, and Angus W Thomson Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Department of Dermatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Department of Physiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA * Corresponding author; email: morelli{at}imap.pitt.edu. Under steady-state conditions, internalization of self antigens embodied in apoptotic cells by peripheral tissue-resident dendritic cells (DC) followed by DC migration and presentation of self-peptides to T cells in secondary lymphoid organs are key steps for induction and maintenance of peripheral T-cell tolerance. We show here that, besides this traffic of apoptotic cells mediated by peripheral tissue-resident DC, splenic marginal zone DC rapidly ingest circulating apoptotic leukocytes, process apoptotic cell-derived peptides into MHC-II molecules, and acquire CD8 during their mobilization to T cell areas of splenic follicles. Since apoptotic cells activate complement and some complement factors are opsonins for phagocytosis and play roles in the maintenance of peripheral tolerance, we investigated the role of complement receptors (CR) in relation to phagocytosis of apoptotic cells by DC. Apoptotic cell uptake by marginal zone DC was mediated in part via CR3 (CD11b/CD18) and, to a lesser extent, CR4 (CD11c/CD18) and was reduced significantly in vivo in hypocomplementemic animals. Following phagocytosis of apoptotic cells, DC exhibited decreased levels of mRNA and secretion of the proinflammatory cytokines interleukin (IL)-1, IL-1ß, IL-6, IL-12p70, and tumor necrosis factor (TNF)-, without any effect on the anti-inflammatory mediator transforming growth factor (TGF)-ß1. This selective inhibitory effect was at least partially mediated through C3bi-CD11b/CD18 interaction. Characterization of apoptotic cell-DC interaction and its outcome provides insight into the mechanism(s) by which apoptotic cells affect DC function without disrupting peripheral tolerance. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Chen, Y.-B. Park, E. Patel, and G. J. 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