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

免疫功能随着年龄的增长而下降，导致老年人对感染的易感性增加， 对疫苗的反应减弱。对新遇到的抗原产生T细胞应答的能力， 免疫应答依赖于T细胞多样性库的维持。衰老是 与小鼠和人的库多样性降低相关。我们之前已经证明， 是幼稚CDS T细胞中库多样性的年龄相关性减少，并且使用小鼠 流感病毒模型已经确定了减少原发性和保护性 老年小鼠对流感病毒免疫力。我们有新的初步数据显示， 干扰还影响CD4 T细胞对流感病毒表位的应答。由于减少了 天真的剧目在老年人，我们假设，老龄化的结果，在更大的贡献， 交叉反应记忆细胞对新感染的反应，这将导致随机反应 在个体中，通常是低亲和力的。为了支持这一点，我们有初步数据显示， 来自未感染流感病毒的老年小鼠的交叉反应性记忆细胞可以对流感病毒表位产生应答， 目的1：我们将确定交叉反应记忆对新感染反应的贡献， 对细胞免疫的影响。在目标2中，我们将侧重于实验性干预措施，以提高 老年小鼠T细胞库和保护性免疫。在该方案的其他项目中， 这些研究将阐明与年龄相关的细胞免疫下降的机制， 这对于为老年人设计更好的疗法和疫苗的目标至关重要。 相关性（参见说明）： 相关性：随着年龄的增长，我们对感染或疫苗接种的反应能力急剧下降。埃尔德里 个体比年轻人更容易感染，呼吸道感染，如 由流感病毒引起的流感是这一群体死亡和住院的主要原因。疫苗是 因此，这是必要的，但不幸的是，老年人也更难以接种疫苗。建议的研究 将确定老年人免疫力下降的机制，并将开始测试 克服这些缺陷，以设计更好的疫苗。

Immune function declines with age, resulting in increased susceptibility of aged individuals to infection and impaired responses to vaccines. The ability to generate T cell responses to newly encountered antigens and to respond to vaccination is dependent on the maintenance of a diverse repertoire of T cells. Aging is associated with reduced repertoire diversity in both mouse and human. We have previously shown that there is an age-associated reduction in repertoire diversity among naive CDS T cells, and using the mouse influenza virus model have defined profound consequences of reduced repertoire for primary and protective immunity of aged mice to influenza virus. We have new preliminary data showing that repertoire perturbations also impact CD4 T cell responses to influenza virus epitopes. Because of reduction of the naive repertoire in aged individuals, we hypothesize that aging results in a greater contribution of fortuitously cross-reactive memory cells to the response to new infections, and that this will lead to stochastic responses in individuals, often of lower avidity. In support of this, we have preliminary data showing that fortuitously cross-reactive memory cells from influenza-naive aged mice can respond to influenza virus epitopes, and in Aim 1 we will determine the contribution of cross reactive memory to the response to new infections, and the implications for cellular immunity. In Aim 2 we will focus on experimental interventions to enhance diversity of the T cell repertoire and protective immunity in aged mice. In the context of other projects in the Program, these studies will address mechanisms underiying the age-associated decline in cellular immunity which is essential for the goal of designing better therapies and vaccines for the elderiy. RELEVANCE (See instructions): Relevance: Our ability to respond to infection or vaccination decreases dramatically as we age. Elderiy individuals are significantly more susceptible to infections than the young, and respiratory infections, such as those caused by influenza virus, are a major cause of death and hospitalization in this group. Vaccines are therefore essential but, unfortunately, the elderiy are also more difficult to vaccinate. The studies proposed will determine the mechanisms underiying decreased immunity of the elderly, and will begin to test ways of overcoming these deficiencies in order to design better vaccines.