Viral infections, and the associated tumors and disease that they cause, are a major source of economic and social burden in Europe. There is an urgent need to understand the basic mechanisms behind their pathogenesis to accelerate the rational design of vaccines and therapeutics. The training of highly skilled immunologists is vital to support this process. Epstein-Barr virus (EBV) is a medically important infection, responsible for a diverse range of severe pathologies, including acute infectious mononucleosis (AIM), head and neck cancers and immuno-proliferative disorders. Cross-reactive memory T cells have recently been found to play a role in mediating EBV-induced AIM. This proposal aims to systematically dissect the mechanisms of CD8 T cell cross-reactivity in children, young adults and the elderly using EBV as an example of viral infection in humans. Using a combination of novel and sophisticated molecular and cellular techniques, these studies will 1) examine the role of T cell cross-reactivity in the development of clonal dominance patterns, 2) identify novel cross-reactive ligands, 3) characterize the functional and phenotypic characteristics of cross-reactive CD8 T cells, and 4) determine the binding kinetics of cross-reactive T cells with various ligands. It is highly likely that these cross reactive T cell responses to EBV only begin to scratch the surface of the prevalence and potential impact of heterologous immunity on vaccines and immunopathology. This training will be carried out in the Selin laboratory that has pioneered the field of heterologous immunity, and in the Price laboratory that has developed unique tools to probe the molecular mechanisms behind these phenomena. This training will provide a solid foundation for the long-term career development of the researcher, and endow her with an essential tool-box of resources, complementary skills and knowledge to perform outstanding research on viral immunopathogenesis in Europe.
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