Influenza is a highly contagious acute respiratory disease that is responsible for the deaths of large numbers of elderly and immunocompromised people each year. Cytotoxic T cells (CTL) play an important role in viral clearance and can provide short-term heterosubtypic immunity, indicating that they could be an effective supplement to antibody-based vaccination. The main advantage of targeting T cell responses is their ability to recognize epitopes in internal viral proteins that are conserved between different strains of virus, however the utility of the approach is limited by the short duration of the immunity that is established. In a recent study, we showed that processed T cell antigens persist in the draining lymph nodes of the respiratory tract for at least two months after infection, where they had a profound influence on local T cell migration and activation in the lungs. Based on these studies, we postulate that prolonged antigen presentation contributes to protective cellular immunity by retaining activated or partially-activated virus-specific CD8 T cells near the site of infection, where they can respond rapidly to reinfection. The studies to test this hypothesis will be divided into three parts:
Aim 1. To determine which CD8 T cells respond to residual viral antigens in the draining lymph nodes.
Aim 2. To identify mechanisms that control retention of virus-specific CD8 T cells in the lung tissues. Recombinant influenza viruses that differ only at a single T cell epitope, and gene targeted mice that lack specific adhesion molecules, will be used to determine how T cell surface antigens that are tightly regulated by T cell receptor (TcR)-signaling influence the retention of antigen-specific CD8 T cells near the site of infection.
Aim 3. To determine how sustained antigen presentation impacts protective immunity and the development of a recall response during reinfection. Two serologically distinct viruses will be used to determine whether prolonged antigen presentation is essential for the maintenance of protective immunity. Primed mice will be joined to uninfected partners and separated after T cell equilibration, to compare the recall responses by migrating and non-migrating CD8 T cells in the presence and absence of residual viral antigens. Together, these studies will greatly increase our understanding of the mechanisms that regulate CD8 T cell responses in the respiratory tract and have important implications for vaccination in the lungs and other mucosal tissues.
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