Aging, T cell repertoire, and cellular immunity to influenza virus

说明(申请人提供)：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。当前提案的一个关键重点是使用具有良好特征的流感病毒感染的小鼠模型来确定老年人对新感染和疫苗的反应能力和记忆力下降的潜在机制。为了制定克服这些缺陷的战略，这些研究是必不可少的。产生T细胞对新遇到的抗原的反应和对疫苗接种的反应的能力取决于T细胞库的多样性的维持。我们之前已经证明，CD8T细胞之间的谱系多样性随着年龄的增长而减少，这对流感病毒的初级免疫和保护性免疫具有深远的影响。由于老年人幼稚T细胞的数量减少和多样性，我们假设衰老导致偶然的交叉反应记忆细胞在对新感染的反应中做出更大贡献，这将导致随机反应，通常亲和力较低，并且可能是有害的或病理性的。为了支持这一点，我们有初步数据表明，来自流感幼稚老年小鼠的偶然交叉反应记忆细胞可以对流感病毒表位做出反应，在目标1中，我们将确定交叉反应记忆对新感染反应的贡献，并评估其对细胞免疫的影响。与衰老相关的另外两个特征良好的缺陷是CD4T细胞功能受损和CD8T细胞记忆不良。然而，老化的CD4T细胞在CD8记忆缺陷发展中的作用在衰老研究中是一个研究不足的领域，将在该提案的目标2中进行检验。综上所述，这些研究将解决与年龄相关的细胞免疫下降的潜在机制，这对于为老年人设计更好的治疗方法和疫苗的目标至关重要。

DESCRIPTION (provided by applicant): Immune function declines with age, resulting in increased susceptibility of aged individuals to infection and impaired responses to vaccines. A key focus of the current proposal is to use a well-characterized mouse model of influenza virus infection to determine mechanisms underlying the decreased ability of aged individuals to respond to and develop memory to new infections and vaccination. These studies are essential in order to develop strategies for overcoming these defects. 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. We have previously shown that there is an age-associated reduction in repertoire diversity among CD8 T cells, which has profound consequences for primary and protective immunity to influenza virus. Because of reduced numbers and diversity of naive T cells 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, often of lower avidity, and perhaps detrimental or pathological. 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 assess the implications for cellular immunity. Two additional well-characterized defects associated with aging are that CD4 T cells are functionally impaired and that poor CD8 T cell memory is generated. However, the contribution of aged CD4 T cells to the development of defective CD8 memory is an understudied area in aging research, and will be examined in Aim 2 of the proposal. Taken together, these studies will address mechanisms underlying the age-associated decline in cellular immunity which is essential for the goal of designing better therapies and vaccines for elderly humans.