Antibodies can be mediators of important biological changes when bound to living cells. We seek to modulate immunity by engaging receptors on cells that regulate the immune system. These studies address the mechanisms underlying the potentiation of the immune response by a novel antibody, sHIgM12, which binds to B7-DC, a B7 family member expressed on dendritic cells (DC). Administration of the antibody in vivo or in vitro potentiates antigen specific responses by T cells. A strong anti-tumor response to B16 melanoma is seen in animals receiving antibody. The antibody does not bind tumor cells or lymphocytes, suggesting that potentiation of the immune response is mediated by physiological changes induced in the bound DC. We have accumulated lines of evidence demonstrating that cross-linking B7-DC on DC transduces a signal activating NF-kappaB and up-regulating expression of immune modulating cytokine IL-12. B7-DC is known as a ligand for receptors on T cells and not as a receptor mediating intracellular signals. Our finding simply that this molecule provides for two-way communication between DC and their environment. Mechanistic issues to be addressed include identification of the molecules expressed by DC that mediate the transduction of signals into the cells, the nature of intracellular signals in DC induced by the antibody, and the influence of the antibody on gene expression, with particular emphasis on chemokine receptors and cytokines. The intercellular interaction of DC with T cells that become activated in vivo and in culture will also be explored with attention to the role of B7-DC in upregulating the ability of antibody treated DC to activate na?ve T cells. Among these functions are those associated with cross-presentation of exogenous antigen by the class I pathway. The requirements for intercellular contact and cytokine release will also be investigated. Our intention is to discern how this antibody functions as an immune potentiator and to glean from these studies approaches to enhance immunity in vivo, while obtaining insight into natural B7-DC functions.
