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，导致老年人对感染和 对疫苗的反应减弱。产生T细胞对新遇到的抗原和 对疫苗的反应取决于T细胞多样性的维持。老龄化是 与老鼠和人类的曲目多样性减少有关。我们之前已经表明，在那里 是幼稚CDS T细胞中与年龄相关的谱系多样性的减少，并使用小鼠 流感病毒模型定义了减少原发和保护性谱系的深远后果 老龄小鼠对流感病毒的免疫力。我们有新的初步数据显示 扰动也会影响CD4T细胞对流感病毒表位的反应。因为减少了 在老年人天真的曲目中，我们假设年龄的增长导致了更大的贡献 记忆细胞对新感染的反应的交叉反应，这将导致随机反应 在个体中，通常具有较低的亲和力。为了支持这一点，我们有初步数据表明，很偶然 流感初生的老年小鼠的交叉反应记忆细胞可以对流感病毒表位做出反应，并且在 目的1我们将确定交叉反应记忆在对新感染的反应中的作用，以及 对细胞免疫的影响。在目标2中，我们将重点放在实验干预上，以增强 衰老小鼠的T细胞库和保护性免疫。在本方案的其他项目范围内， 这些研究将解决与年龄相关的细胞免疫下降的潜在机制，即 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。

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 underlying the age-associated decline in cellular immunity which is essential for the goal of designing better therapies and vaccines for the elderly.