Impact of aging on the T cell repertoire and cellular immunity to influenza virus

描述(申请人提供)：免疫系统对病原体挑战或疫苗接种的反应能力随着年龄的增长而急剧下降。由于在感染或接种期间T细胞对新遇到的抗原的反应依赖于不同的T细胞库，我们假设老年人免疫功能受损的部分原因是T细胞多样性的下降。为了解决这一假设，我们正在利用一个成熟的流感病毒小鼠模型来评估免疫功能下降对病原体挑战的有效反应的影响。我们的初步数据证实，在NAOVE CD8 T细胞中，存在与年龄相关的谱系多样性降低。此外，我们还进行了开创性的观察，即老年小鼠优先丧失对特定流感病毒表位的反应能力，这与这些表位的T细胞前体频率较低有关。这导致在新发流感病毒感染后出现“谱系上的漏洞”，这与通过异型挑战评估的保护性免疫受损有关。显然，这些发现对为老年人制定合理的疫苗接种策略具有深远的影响。然而，减少的曲目多样性在多大程度上直接影响病毒清除尚不清楚。我们也不知道是否存在类似的与年龄相关的CD4谱系的扰动，以及这在多大程度上影响了CD4的反应，以及CD8功能记忆的产生和维持。具体目的就是为了回答这些问题。拟议的研究将通过加强我们对衰老对CD4和CD8T细胞的谱系和反应性的影响的理解来推动该领域的发展。产生的数据将对开发有效的老年人疫苗产生重要影响。公共卫生相关性：随着年龄的增长，免疫系统应对病原体挑战或接种疫苗的能力急剧下降。老年人明显比年轻人更容易感染，而且众所周知很难成功接种疫苗。因此，呼吸道病毒感染，如由流感病毒介导的感染，是老年人死亡和住院的主要原因。目前申请中提出的研究将确定流感病毒感染小鼠模型免疫反应性降低的机制。所产生的数据将为制定适合老年人的新疫苗接种策略提供必要的信息。

DESCRIPTION (provided by applicant): The capacity of the immune system to respond to pathogen challenge or vaccination decreases dramatically with age. Since the initiation of T cell responses to newly encountered antigens during infection or vaccination is dependent on a diverse repertoire of T cells, we hypothesize that impaired immune function in the aged is due, in part, to declining T cell diversity. To address this hypothesis, we are exploiting a well- developed mouse model of influenza virus to assess the impact of declining immune function on the effective response to pathogen challenge. Our preliminary data confirm that there is an age-associated reduction in repertoire diversity among naove CD8 T cells. In addition, we have made the seminal observation that there is a preferential loss of the ability of aged mice to respond to specific influenza virus epitopes and that this correlates with a low precursor frequency of T cells for these epitopes. This results in the development of "holes in the repertoire" following de novo influenza virus infection, which correlated with impaired protective immunity assessed by heterosubtypic challenge. Clearly, these findings have profound implications for the development of rational vaccination strategies for the elderly. However, the extent to which reduced repertoire diversity directly impacts viral clearance is not known. We also don't know whether there are similar age-associated perturbations of the CD4 repertoire, and to what extent this impacts CD4 responses, as well as the generation and maintenance of functional CD8 memory. The Specific Aims are directed toward answering these questions. The proposed studies will advance the field by enhancing our understanding of the impact of aging on the repertoire and reactivity of CD4 and CD8 T cells. The data generated will have important implications for the development of effective vaccines for the elderly. PUBLIC HEALTH RELEVANCE: The capacity of the immune system to respond to pathogen challenge or vaccination decreases dramatically as we age. Elderly individuals are significantly more susceptible to infections than the young and notoriously difficult to successfully vaccinate. Consequently, respiratory virus infections, such as those mediated by influenza virus, are a major cause of death and hospitalization in the elderly. The studies proposed in the current application will determine the mechanisms underlying decreased immune responsiveness in a mouse model of influenza virus infection. The data generated will provide essential information for the development of new vaccination strategies suitable for aged individuals.