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

衰老、T 细胞库和对流感病毒的细胞免疫

• 批准号: 8485491
• 负责人: Marcia A Blackman
• 金额: $ 18.89万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485491
• 关键词: Address; Age; Aging; Animals; Antigens; Area; Avidity; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Aging; Cells; Cellular Immunity; Characteristics; Data; Defect; Dependence; Development; Elderly; Epitopes; Generations; Goals; Human; Immune; Immunity; Individual; Infection; Influenza; Lead; Maintenance; Memory; Modeling; Mus; Predisposition; Rejuvenation; Relative (related person); Research; Role; T cell response; T memory cell; T-Lymphocyte; Thymectomy; Vaccinated; Vaccination; Vaccine Therapy; Vaccines; Viral; Virus Diseases; aged; cell age; design; germ free condition; immune function; improved; influenzavirus; insight; keratinocyte growth factor; man; mouse model; research study; response; restoration; therapeutic vaccine

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.

描述（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以及对疫苗的反应受损。当前提案的一个重点是使用特征明确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反应和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。 T 细胞对新遇到的抗原产生反应以及对疫苗接种作出反应的能力取决于 T 细胞多样化库的维持。我们之前已经证明，CD8 T 细胞的库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产生深远的影响。由于老年人中幼稚 T 细胞的数量和多样性减少，我们假设衰老导致偶然交叉反应记忆细胞对新感染的反应做出更大的贡献，并且这将导致随机反应，通常亲合力较低，也许是有害的或病态的。为了支持这一点，我们有初步数据表明，来自未经流感处理的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 细胞记忆能力较差。然而，衰老的 CD4 T 细胞对 CD8 记忆缺陷的形成的贡献是衰老研究中尚未研究的领域，将在提案的目标 2 中进行研究。总而言之，这些研究将解决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。