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C1q Differentially Modulates Phagocytosis and Cytokine Responses during Ingestion of Apoptotic Cells by Human Monocytes, Macrophages, and Dendritic Cells¹

Deborah A. Fraser,^2* Amanda K. Laust,^2* Edward L. Nelson, and Andrea J. Tenner³

*Department of Molecular Biology and Biochemistry and Department of Medicine, Institute for Immunology, University of California, Irvine, CA 92697

C1q, the first component of the classical complement pathway, is also a pattern recognition receptor involved in the recognition and clearance of apoptotic cells. C1q deficiency in humans leads to development of lupus-like autoimmune disease, and it has been speculated that impaired clearance of apoptotic cells may contribute to disease development. Since phagocytes initiate specific and appropriate immune responses as a result of initial ligand-receptor interactions, regulation of gene expression by C1q may also contribute to the sculpting of an immune response to the ingested "self-Ags." In this study, the role of C1q in apoptotic cell clearance and subsequent modulation of cytokine release by phagocytes was assessed including donor matched human monocytes, monocyte-derived macrophages (HMDMs), and dendritic cells (DCs). First, C1q binding is much greater to late compared with early apoptotic cells. Second, C1q binding to apoptotic cells significantly enhanced the levels of ingestion by monocytes but had no effect on HMDM and DC uptake. Third, in the presence of serum, C1q bound to apoptotic cells, activated the complement pathway, leading to C3b deposition, and enhancement of uptake of apoptotic cells by monocytes, HMDMs, and DCs. Finally, although C1q, either immobilized on a plate or bound to apoptotic cells, modulates the LPS-induced cytokine levels released by human monocytes, HMDMs, and DCs toward a more limited immune response, both the degree and direction of modulation differed significantly depending on the differentiation state of the phagocyte, providing further evidence of the integration of these cell- and environment-specific signals in determining appropriate immune responses.

³ Address correspondence and reprint requests to Dr. Andrea J. Tenner, University of California Irvine, Department of Molecular Biology and Biochemistry, 3205 McGaugh Hall, Irvine, CA 92697-3900. E-mail address: atenner{at}uci.edu

¹ This work was supported by National Institutes of Health Grant AI41090 (to A.J.T.). The project described was also supported by Grant Number T32CA009054 from the National Cancer Institute (to A.K.L. and E.L.N.) and the Chao Family Comprehensive Cancer Center at University of California Irvine (to E.L.N.). Support for obtaining human blood products used in this study was provided in part by Public Health Service Research Grant M01RR00827.

² D.A.F. and A.K.L. contributed equally to this work.