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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;
Division of Rheumatology, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and
Faculty of Psychology, University of Milano-Bicocca, Milan, Italy
To activate T cells effectively, dendritic cells (DCs) must provide three separate signals, MHC-Ag, costimulatory molecules (such as CD80 and CD86), and proinflammatory cytokines (such as IL-12). These three signals are up-regulated in the presence of "danger signals" such as LPS or viral nucleic acids. Evidence suggests that DCs providing only the first two of these signals cannot successfully stimulate T cells. Apoptotic cells have been proposed to suppress DC immunogenicity through the ligation of apoptotic cell receptors. Complement receptor 3 (CR3) and CD36 have been suggested to be important in this process, although the mechanism by which this modulation occurs is still unclear. We demonstrate that ligation of CR3, but not CD36, directs DCs to increase surface MHC and costimulatory molecules, while suppressing inflammatory cytokine release. CR3 modulation of DCs does not require a type I IFN response, does not involve the specific regulation of the MyD88- or Toll/IL-1R domain-containing adaptor-inducing IFN-
-dependent TLR signaling pathways, and occurs even in the absence of danger signals. The functional outcome of this process is poor Ag-specific stimulation of CD4 and CD8 T cells by CR3-ligated DCs both in naive response as well as upon subsequent challenge with normal DCs. We propose that CR3 provides a "nondanger" signal that suppresses the stimulatory capacity of DCs.
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 Institutes of Health (NIH; Grant T32-HD0043021) and S.G. was supported by the Lupus Foundation Southeastern Pennsylvania Chapter, the Arthritis Foundation (Innovative Grant), and the NIH (NIH/National Institute of Allergy and Infectious Diseases Grant AI049892).
2 Address correspondence and reprint requests to Dr. Edward M. Behrens, Children’s Hospital of Philadelphia, 3615 Civic Center Boulevard, Abramson Research Center 1102, Philadelphia, PA 19104-4318. E-mail address: behrens{at}email.chop.edu
3 Abbreviations used in this paper: DC, dendritic cell; CR3, complement receptor 3; Tg, transgenic; BMDC, bone marrow-derived DC; TRIF, Toll/IL-1R domain-containing adaptor-inducing IFN-; SA, streptavidin; MHC I, MHC class I; MHC II, MHC class II.
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