This proposal is designed to investigate the CD8+ T cell response to Type A Influenza virus infection in the murine model, and the factors which regulate the initial activation and subsequent proliferative expansion of primary CD8+ T cells into effector cytolytic T cells. The experimental approach is based on our recent evidence characterizing the response of respiratory dendritic cells (RDC) to influenza and our analysis of the proliferative response of responding CD8+ T cells in the draining lymph nodes (DLN) and infected lungs.
Aim 1 of this proposal focuses on the contribution of both migrant RDC and lymph-node resident DC (in the DLN) in the presentation of viral antigen to naive CD8+ T cells using complementary in vitro and in vivo methodologies.
Aim 2 will build on our recent evidence indicating an extremely rapid initial division rate (cell cycle time of 2-3 hrs) for CD8+ T cells responding in vivo in the DLN to infection. Studies are proposed to identify and characterize the factors which control CD8+ T cell division rate (cell cycle time) and the contribution of the form/type of antigenic stimulus to the regulation of CD8+ T cell division.
Aim 3 will follow- up on our recent findings demonstrating proliferative expansion of influenza-specific effector CD8+ T cells in the lungs of infected animals. Research efforts will be focused on the contribution of CD11 c+ RDC to the regulation of activated T cell proliferation, as well as on the site and the role of viral antigen in this process. These studies should provide fundamental information on the control of T lymphocyte cell cycle, and new insight into the activation and expansion of anti-viral effector activity by virus-specific CDS* T cells. These studies should both help determine the most efficient way to activate CD8+ T cells during vaccination against respiratory tract viruses like influenza, and provide a framework to allow us to generate the greatest number of immune T cells to boost the immune system and protect from infection. Finally, by understanding what influenza-specific CD8+ T cells do in the infected lungs (and how they do it), we will begin to understand how viruses like influenza can subvert/suppress the immune system and produce lethal infection.
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