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Opsonization of Apoptotic Cells by Autologous iC3b Facilitates Clearance by Immature Dendritic Cells, Down-regulates DR and CD86, and Up-regulates CC Chemokine Receptor 7

Inna Verbovetski¹, Hila Bychkov¹, Uriel Trahtemberg¹, Itzhak Shapira², Mara Hareuveni², Ofira Ben-Tal², Ina Kutikov², Oranit Gill¹ and Dror Mevorach^1,2

¹ The Laboratory for Cellular and Molecular Immunology, Rheumatology Unit, Department of Medicine, Hadassah Hospital and the Hebrew University
² Sourasky Medical Center, Jerusalem 91120, Israel

Address correspondence to Dror Mevorach, The Laboratory for Cellular and Molecular Immunology, Department of Medicine Hadassah University Hospital, Kiryat Hadassah, P.O. Box 12000, Jerusalem 91120, Israel. Phone: 972-2-677-6896; Fax: 972-2-643-3935; E-mail: mevorachd{at}hadassah.org.il

Immature dendritic cells (iDCs) do not mature after uptake of apoptotic cells and may play a role in the induction of peripheral tolerance to self antigens derived from apoptotic material. The integrins, vß3, vß5, and the scavenger receptor, CD36, have been shown to mediate uptake of apoptotic cells by iDCs. However, it is not known whether the complement system, also takes part in this process. In this study we investigated the ability of iDCs to bind to apoptotic cells opsonized by iC3b. Monocyte-derived dendritic cells were offered apoptotic Jurkat cells opsonized by autologous iC3b and labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanineperchlorate. A significant increase (P < 0.001) in the amount of cleared apoptotic cells was seen at low ratios. Despite increased efficiency of uptake, interaction between iC3b-opsonized apoptotic cells and iDCs down-regulated the expression of major histocompatibility complex class II, CD86, CC chemokine receptor (CCR)2, CCR5, and ß2-integrins (P < 0.001), and up-regulated expression of CCR7 (P < 0.001). In addition, iDC maturation responses to CD40L and lipopolysaccharide were significantly inhibited. We conclude that opsonization of apoptotic cells by iC3b induces tolerant iDCs that are able to migrate to lymph nodes.

Key Words: apoptosis • dendritic cells • complement • tolerance • autoimmunity

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