Targeting Dendritic Cells for Enhanced Musocal Immunity

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Dendritic Cells (DCs) are specialized to capture and process antigens in vivo, converting proteins to peptides that are presented on major histocompatibility complex (MHC) molecules and recognized by T cells. Maturation and subsets allow DCs to control the diverse immune responses. To harness DCs for vaccination, we have made high affinity monoclonal antibodies against more than ten DC surface molecules. We have shown DCs control the quality of immune responses by taking up antigens through different DC-lectins. Our overall long-term goal is the development of novel human vaccines based on in vivo DC-targeting. The current focus is on mucosal immunity because mucosa is a major site of invasion as well as replication of pathogens, including influenza virus. Thus, priming of two major effectors, B cells and CD8+ T cells, with mucosal homing capacity is expected to limit viral replication, resulting in reduced disease burden. Furthermore, induction of CD4+ T cells with helper functions for B cells or CTLs will enhance the magnitude and the quality of mucosal homing effectors. The current objective to determine novel DC-targeting vaccines that prime mucosal homing antibody-secreting plasma cells and polyfunctional high avidity CD8+ T cells with broad specificity with the help from appropriate type of CD4+ T cells. Hypothesis: Antigen-specific mucosal immunity can be efficiently induced by a DC-targeting vaccine composed of a unique combination of a specific anti-DC receptor antibody, antigen, and DC activator. AIM 1: To identify a combination of anti-DC fusion protein and DC activator that allows DCs to induce potent antigen-specific mucosal antibody responses in vitro. AIM 2: To identify a combination of anti-DC fusion protein and DC activator that allow DCs to induce polyfunctional and mucosal-homing CD8+ T cells in vitro. AIM 3: To identify combinations of anti-DC fusion protein and DC activator that induce helper CD4+ T cells for potent mucosal humoral responses and CTL responses. Thus, we will establish an optimal combination(s) of anti-DC fusion proteins and DC activators which potently induce mucosal antibody and/or CTL responses.