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Prepublished online as a Blood First Edition Paper on September 5, 2002; DOI 10.1182/blood-2002-06-1769.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 611-620
IMMUNOBIOLOGY
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. Zahorchak,
Alison J. Logar,
Glenn D. Papworth,
Zhiliang Wang,
Simon C. Watkins,
Louis D. Falo Jr, and
Angus W. Thomson
From the Thomas E. Starzl Transplantation Institute and
Department of Surgery, Department of Dermatology and University of
Pittsburgh Cancer Institute and Department of Physiology and Center for
Biological Imaging, University of Pittsburgh Medical Center, PA.
Under steady-state conditions, internalization of self-antigens
embodied in apoptotic cells by dendritic cells (DCs) resident in
peripheral tissue 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 DCs, splenic marginal zone DCs rapidly ingest
circulating apoptotic leukocytes, process apoptotic cell-derived peptides into major histocompatibility complex class II (MHC-II) molecules, and acquire CD8 during their mobilization to T-cell areas
of splenic follicles. Because 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 (CRs) in relation to phagocytosis of apoptotic
cells by DCs. Apoptotic cell uptake by marginal zone DCs 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, DCs exhibited decreased
levels of mRNA and secretion of the proinflammatory cytokines
interleukin 1 (IL-1), IL-1 , IL-6, IL-12p70, and tumor necrosis
factor (TNF-), without effect on the anti-inflammatory mediator
transforming growth factor 1 (TGF-1). 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 mechanisms by which apoptotic cells
affect DC function without disrupting peripheral tolerance.
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