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Published online before print April 14, 2006
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*Clinical Immunology Unit and Cancer Gene Therapy Unit, Cancer Immunotherapy & Gene Therapy Program, H. San Raffaele Scientific Institute, Milano, Italy; Istituto Clinico Humanitas, Rozzano, Italy; Centro di Eccellenza per l’Innovazione Diagnostica e Terapeutica (IDET), Institute of General Pathology, University of Milan, Italy; and ¶Vita-Salute San Raffaele University, Milano, Italy
@ To whom correspondence should be addressed. E-mail: rovere.patrizia{at}hsr.it.
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Abstract |
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Pentraxins (PTX) and complement belong to the humoral arm of the innate immune system and have essential functions in immune defense to microbes and in scavenging cellular debris. The prototypic long PTX, PTX3, and the first component of the classical complement pathway, C1q, are innate opsonins involved in the disposal of dying cells by phagocytes. Whether the interaction between various innate opsonins impacts on their function is not fully understood. We show here that characterized Toll-like receptor (TLR) ligands elicit the production of C1q and PTX3 by immature dendritic cells (DC). Moreover, these molecules bind to dying cells with similar kinetics, although they recognize different domains on the cell membranes. PTX3 binds in the fluid phase to C1q, decreasing C1q deposition and subsequent complement activation on apoptotic cells. C1q increases the phagocytosis of apoptotic cells by DC and the release of interleukin-12 in the presence of TLR4 ligands and apoptotic cells; PTX3 inhibits both events. Moreover, PTX3 inhibited the cross-presentation of the MELAN-A/melanoma antigen-reactive T cell 1 tumor antigen expressed by dying cells, even in the presence of C1q. These results suggest that interaction of C1q and PTX3 influences the clearance of apoptotic cells by DC. The coordinated induction by primary, proinflammatory signals of C1q and PTX3 and their reciprocal regulation during inflammation influences the clearance of apoptotic cells by antigen-presenting cells and possibly plays a role in immune homeostasis.
Key Words: Toll-like receptor • a systemic lupus erythematosus • lipopolysaccharide
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