Many viruses are potent inducers of T cell responses, resulting in the generation of high levels of CD8 cytotoxic T lymphocytes (CTL). T cell mediated immune responses not only assist in clearing infections but can also lead to symptomatic disease and pathogenesis, and this can vary significantly in severity between individuals. In nature the host has a history of multiple sequential infections and develops memory T cell pools of significant size and complexity. My previous research using a mouse system which mimics these natural conditions has shown that these memory T cell populations are not dormant T cell reservoirs but are, in fact, continuously cycling. They are also frequently cross-reactive with other unrelated pathogens and can also be reactivated to participate in responses to new unrelated viruses, resulting in either protective immunity or severe immunopathology. These results led us to propose an immunological network whereby CD8 T cells often crossreact with more than one antigen, and where memory T cell pools are continually being modified as they are stimulated by and contribute to the immune responses against putatively unrelated pathogens. Isolated reports exist of crossreactive human T cell clones, and preliminary work in this project shows that there is crossreactivity between a very common EBV epitope (BMLF1) and an influenza A epitope (M1). However, it is unclear what the magnitude of such crossreactive T cell responses are in humans. This type of crossreactivity may partially explain variations in pathogenesis caused by the same virus, and knowledge of such crossreactivity may be important for future vaccine development. The purpose of this study is to systematically examine whether crossreactive T cell responses are common in human virus infections, focusing on acute and memory CD8 T cell responses to EBV, with the long term goal of determining if they pay a role in pathogenesis. These studies will test the hypothesis that 1) there is reactivation of potentially crossreactive memory T cells to FLU or CMV during acute EBV infection, 2) the same TcR on dual reactive T cell clones in recognizing both epitopes and receiving qualitatively different signals from each epitope, and 3) the frequency of crossreactive memory T cells is higher in older, antigen experienced individuals.
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