Naive CD8 T cell repertoire in aged mice

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This proposal is in response to PAR-02-049, regarding "Improving Health and Quality of Life of Older People" category 5, vaccine development. Waning immunity in the elderly is an important medical problem. There is an urgent need to understand mechanisms underlying immune dysfunction associated with aging, so that preventative and therapeutic strategies can be developed. Influenza viruses represent a major cause of illness in the United States. Thc increased mortality over the last two decades is largely due to the increasing longevity of the human population, as the elderly are more susceptible to infection, and are not fully protected by current vaccination strategies. It is critical that effective vaccination strategies for the elderly be developed, not only as protection from natural yearly influenza epidemics, but also from potential bioterrorism attacks. An age-related defect in the activation of naive CD4+ T cells has been described. However, there is less evidence for a functional defect of CD8+ T cells. It has been postulated but not proven that a contributing factor to the defective cellular immune response in the aged is a loss of diversity in the CD8+ T cell repertoire. The goals of the proposed studies are two fold. First, we will compare thc diversity of the halve CD8+ T cell repertoire in young and aged mice, by DNA spectratype and sequence analysis. Second, we will examine the diversity in the CD8+ cellular immune response of aged mice following primary influenza virus vaccination, by DNA spectratype analysis. Taken together, these studies will determine whether age-associated loss of repertoire diversity plays a role in immune dysfunction. The results have relevance for determining the feasibility of some vaccination strategies for the elderly, in which defined viral proteins or epitopes may be used as immunogens, as significantly reduced repertoire diversity in the aged may result in "holes" in the T cell repertoire.