Antigen presentation by MHC class I molecules to CD8 T cells is a major pathway by which the acquired immune system detects and eliminates virus infected cells. All nucleated cells express MHC class I molecules and are thus potentially capable of direct antigen presentation to CD8 T cells upon infection. However, several, but not all, recent studies suggest that predominantly DCs (or a specific subset of DCs) are uniquely required for in vivo priming of CD8 T cell to virus. Because pathogens may not directly infect these requisite DCs, cross presentation pathways have been proposed;in essence, the infected cell may not be the primary antigen presenting cells. Additionally, for many arthropod-transmitted viruses, virus-specific antigens may require transfer from migratory DCs in the skin to lymph node resident DCs to efficiently prime CD8 T cells. However, the mechanism by which pathogen-specific antigens are shuttled from the infected cells to DCs or between DC subsets is unknown. Not surprisingly, these same issues of direct presentation vs cross-presentation also apply to CD8 T cell responses to tumors or following DNA vaccination. The experiments proposed in this application will address outstanding questions of the molecular and cellular basis of in vivo priming of CD8 T cells against viruses and following DNA vaccination. As unique probes of antigen presentation pathways in virus immunity, we have engineered MHC class I molecules as peptide-preloaded single chains (or SCTs), defined immunodominant epitopes detected by CD8 T cells after West Nile virus (WNV) infection, and characterized novel T cell receptor mimic monoclonal antibodies that recognize MHC class I loaded with WNV peptides. These reagents will be used to dissect the cellular and immunologic mechanisms by which protective CD8 T cell responses against WNV infection are generated.
This grant will study how the immune system detects virus infected cells. More specifically, we will identify which cells of the body get infected with West Nile virus and which of these cells are required to generate an immune response to clear the infection.
