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* Laboratory of Dendritic Cell Biology, Division of Rheumatology, Joseph Stokes, Jr. Research Institute, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318;
Division of Rheumatology, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4318;
Department of Surgery, Children’s Hospital of Philadelphia, Philadelphia, PA 19104-4318
A number of recent studies show that activation of CR3 on dendritic cells (DCs) suppresses TLR-induced TNF-
and IL-12 production and inhibits effective Ag presentation. Although the proposed physiologic role for these phenomena is immune suppression due to recognition of iC3b opsonized apoptotic cells by CR3, all of the aforementioned investigations used artificial means of activating CR3. We investigated whether iC3b opsonized apoptotic cells could induce the same changes reported with artificial ligands such as mAbs or iC3b-opsonized RBC. We explored the kinetics of iC3b opsonization in two models of murine cell apoptosis, 
-irradiated thymocytes and cytokine deprivation of the IL-3 dependent cell line BaF3. Using a relatively homogenous population of early apoptotic cells (IL-3 deprived BaF3 cells), we show that iC3b opsonized apoptotic cells engage CR3, but this interaction is dispensable in mediating the anti-inflammatory effects of apoptotic cells. TLR-induced TNF- and IL-12 production by bone marrow-derived DCs occurs heterogeneously, with apoptotic cells inhibiting only certain populations depending on the TLR agonist. In contrast, although apoptotic cells induced homogeneous IL-10 production by DCs, IL-10 was not necessary for the inhibition of TNF- and IL-12. Furthermore, because the ability of iC3b opsonization to enhance phagocytosis of apoptotic cells has been controversial, we report that iC3b opsonization does not significantly affect apoptotic cell ingestion by DCs. We conclude that the apoptotic cell receptor system on DCs is sufficiently redundant such that the absence of CR3 engagement does not significantly affect the normal anti-inflammatory processing of apoptotic cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 E.M.B. was supported by the National Institute of Health (NIH Grant T32-HD0043021) and an Arthritis Foundation Post-Doctoral Fellowship, and S.G. by the Lupus Foundation Southeastern Pennsylvania Chapter, Arthritis Foundation (Innovative Grant).
2 Address correspondence and reprint requests to Dr. Edward M. Behrens, Children’s Hospital of Philadelphia, 3615 Civic Center Boulevard, ARC 1102, Philadelphia, PA 19104-4318. E-mail address: behrens{at}email.chop.edu
3 Abbreviations used in this paper: SLE, systemic lupus erythematosus; DC, dendritic cell; FSC, forward scatter; MdFI, median fluorescence intensity; BMDC, bone marrow derived DCs; CR3, complement receptor 3.
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