An exciting new area of research in my laboratory is investigating strategies to regulate immune response by engaging immunocompetent cells with cross-linking antibodies. Recently, we discovered a human monoclonal IgM antibody that binds the co-stimulatory B7 family member B7-DC. Our hypothesis is that the IgM antibody cross-links B7-DC transducing signals that activate predetermined programs in this population of antigen-presenting cells. Antibody binding induces dramatic changes in dendritic cell function, both in vitro and in vivo. Following binding of B7-DC on dendritic cells by the IgM antibody a variety of kinases and adapter molecules are activateed leading to NF-kappaB translocation to the nucleus, calcium molbilzation, and the activation of cytoskeletal rearrangements governing pinocytosis. Cellular activation leads to changes in the expression of a variety of chemokine and cytokine genes and proteins. Co-stimulatory molecules and chemokine receptors become expressed on the cell surface of the antibody treated dendritic cells. Activation of dendritic cells by cross-linking B7-DC results in functional changes influencing the ability of these antigen-presenting cells to activate na?ve T cells, alter the polarity of ongoing T cell responses (Th1 relative to Th2), and alter broader immune functions such as anti-tumor and allergic immune responses. Remarkably, the human monoclonal antibody being investigated binds to conserved features of mouse and human B7-DC, reproducing the gene activation patterns and T cell activation properties seen in the mouse when human dendritic cells are manipulated. Future work will address how cross-linking B7-DC transduces signals in dendritic cells and how modulation of dendritic cell function can be used to understand and to manipulate host responses to intervene in immune conditions such as cancer immunity, allergic responses, and autoimmunity.

Other projects in thelaboratory include studies on anti-viral immunity in the central nervous system. A small set of virus-derived peptide antigens is highly immunogenic inducing strong, protective T cell-mediated responses that lead to virus clearance. We would like to learn what distinguishes peptides that elicit strong immunity from those that do not. We are also interested in understanding the mechanisms employed by the immune system to clear persistent virus infections in the CNS without damaging the brain tissues. The expression of MHC antigen-presenting molecules in the brain appear to be a key factor in determining virus resistance. Recent findings in the laboratory demonstrate that the tissue distribution of MHC expression during virus expression is a very important factor in determining whether the immune system is mobilized and can clear the virus. Elegant mouse models developed using knockout, transgenic, and mutant animals are being used to pursue these questions.

The laboratory has a long standing interest in the natural origin of MHC diversity and in defining the functional significance the the extreme frequency of variants selectively maintained in populations. Studies are ongoing using spontaneous MHC mutants in mice to investigate the mechanisms generating diveristy and the functional significance of these saltatory changes in the structures of MHC antigen presenting molecules.

A new interesting line of investigation arose serendipitously out of experiments using transgenes to manipulate MHC gene expression. An unusual mouse was generated that expresses the transgene in a novel manner marking T cells as they undergo differentiation events in the periphery. We determined that transgene expression marks memory cells in young animals and its expression increases over time as mice age. Our hypothesis is that the transgene serves as a surrogate marker for key events in the life of T cells and can be used to understand molecular events that govern the transition between naive or activated T cells and the formation of memory cells. We may also be able to use this marker to dissect events governing senescence of the immune system.