Work outlined in this proposal addresses the hypotheses that virus-specific CD8+ T cell repertoires change quantitatively and qualitatively over time following acute infection, and that differences in virus-specific CD8+ T cell repertoires may influence the control of viral replication or disease pathogenesis. Changes in theEBV- specific CD8+ T cell repertoire over time may be based on properties of EBV-specific CD8+ T cell clones (specificity, T cell receptor usage, cytokine receptors and expression of survival factors) and ongoing antigen exposure. Collaborative work with Drs. Selin and Welsh (Project 3) will test the hypothesis that age-related diffe/ences in the evolution of cross-reactive CD8+ T lymphocyte responses will be observed and may be influenced by prior (or lack of prior) exposure to other viral pathogens. To address these hypotheses, we will investigate the evolution of CD8+ T lymphocyte responses during the early (induction) and long-term (maintenance) phases of the immune response in infants, children, adolescents, and adults. The following Specific Aims will be addressed: 1) To define the relationship between the virus-specific T cell receptor repertoires at serial time points from the acute through the memory phases of the T cell response; 2) To define the relationship between the expression of cytokine receptors or survival factors during the acute phase of the T cell response and T cell clonal persistence into the memory pool; 3) To define the relationship between the functional profiles of virus-specific T cells during the acute phase of the T cell response and their maintenance of proliferative and cytolytic capacity during the long-term memory phase; and 4) To correlate EBV-specific CD8+ T cell frequencies and functional properties over time with blood viral load, pharyngeal shedding, and disease severity. This project directly supports the overall objective of the Program Project by characterizing the induction, evolution, and maintenance of virus-specific CD8+ T lymphocyte responses to a persistent viral infection. Our investigation of memory CD8+ T lymphocyte responses resulting from a persistent viral infection with repeated but changing exposure to viral antigens will complement Drs. Rothman's and Ennis' investigation of memory CD8+ T lymphocyte responses resulting from receipt of yellow fever or vaccinia vaccines in Project 3. Altogether, these studies will help us to understand the timing of and factors that control the evolution of human antiviral CD8+ T cell responses from the acute effector phase into long-term memory. These studies will also help us to understand how antigen-specific or cross-reactive CD8+ T cells may contribute to either viral control or disease. Ultimately, we hope that they will help to inform the development of antiviral vaccines that afford long-term protection against infection or disease, while minimizing the potential adverse effects of these vaccines.
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