: This is a revised application from Dr. Liisa Selin to study cross-reactive immunity to systemic and mucosal viral infections. Many viruses, such as Epstein Barr virus (EBV), cytomegalovirus (CMV), and influenza (FLU) virus, are potent inducers of T cell responses, resulting in the generation of high levels of CD8 cytotoxic T lymphocytes (CTL). These virus-specific T cell mediated immune responses can lead to symptomatic disease and pathogenesis, the severity of which can vary significantly between individuals. Studies of both human and mouse viral infections have tended to focus on whether a T cell response is required to clear a particular virus, on the kinetics of virus clearance in relation to the T cell response, and on T cell epitope specificity for individual viruses. However, in nature the host has a history of multiple infections in sequence and memory T cell pools of significant size and complexity. Our work in the mouse system has shown that these memory T cell populations are not dormant T cell reservoirs, but are, in fact continuously cycling and can actively participate in responses to new unrelated viruses. The investigator has found that acute virus infections in mice elicit CTL cross-reactive with alloantigens and with viruses from previous infections. A heterologous viral infection stimulates T cell responses that may prime an immune response and either provide some protective immunity to a second unrelated viral infection or else induce severe immunopathology. Subsequent to a second viral infection, the memory CTL response to the first virus is diminished and qualitatively altered. The investigator proposes an immunological network whereby CD8 T cells often cross-react with more than one antigen, and where memory T cell pools are continually being modified as they contribute to the immune responses against putatively unrelated pathogens. This type of cross-reactivity may partially explain the individual variation in pathogenesis caused by the same virus, and knowledge of such cross-reactivity may be important for future vaccine development. The purpose of this study is to systematically examine in the mouse model whether these cross-reactive T cell responses play a role in protective immunity and immunopathogenesis in both mucosal and systemic virus infections.