Naive CD8 T cell repertoire in aged mice

这项建议是对PAR-02-049关于“改善老年人的健康和生活质量”第5类疫苗开发的回应。老年人免疫力下降是一个重要的医学问题。迫切需要了解与衰老相关的免疫功能障碍的潜在机制，以便开发预防和治疗策略。流感病毒是美国疾病的主要原因。过去20年死亡率上升的主要原因是人口寿命延长，因为老年人更容易受到感染，而且目前的疫苗接种战略没有提供充分的保护。为老年人制定有效的疫苗接种战略是至关重要的 发展起来的，不仅是为了预防每年的自然流感流行，而且是为了防止潜在的 生物恐怖主义袭击。一个年龄相关的缺陷，在幼稚的CD4+T细胞的激活已被描述。然而，CD8+T细胞功能缺陷的证据较少。CD8+T细胞多样性的丧失是导致老年人细胞免疫反应缺陷的一个重要因素，但尚未得到证实。拟议研究的目标有两个。首先，我们将通过DNA谱型和序列分析，比较年轻和老年小鼠CD8+T细胞亚群的多样性。其次，我们将通过DNA图谱分析，检测老年小鼠在初次接种流感病毒疫苗后CD8+细胞免疫反应的多样性。综上所述，这些研究将确定与年龄相关的谱系多样性丧失是否在免疫功能障碍中发挥作用。结果是 与确定一些老年人疫苗接种策略的可行性有关，在这些策略中，确定的病毒蛋白或表位可用作免疫原，因为显著降低老年人的免疫谱系多样性可能导致T细胞谱系的“空洞”。

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.