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

描述（由申请人提供）：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。当前建议的一个重点是使用具有良好特征的流感病毒感染小鼠模型来确定老年人对新感染和疫苗接种的反应和发展记忆能力下降的机制。这些研究对于制定克服这些缺陷的策略至关重要。对新遇到的抗原产生T细胞反应和对疫苗产生反应的能力依赖于T细胞多样性的维持。我们之前的研究表明，CD8 T细胞的库多样性与年龄相关，这对流感病毒的初级和保护性免疫具有深远的影响。由于老年个体中初始T细胞的数量和多样性减少，我们假设衰老会导致偶然性交叉反应记忆细胞对新感染反应的更大贡献，这将导致随机反应，通常是较低的，可能是有害的或病理的。为了支持这一点，我们有初步数据显示，来自流感初发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反应，在Aim 1中，我们将确定交叉反应性记忆对新感染反应的贡献，并评估其对细胞免疫的影响。另外两个与衰老相关的明显缺陷是CD4 T细胞功能受损和CD8 T细胞记忆不良。然而，衰老的CD4 T细胞对CD8记忆缺陷的发展的贡献在衰老研究中是一个未被充分研究的领域，将在提案的Aim 2中进行研究。综上所述，这些研究将解决与年龄相关的细胞免疫力下降的潜在机制，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.