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: 8185622
• 负责人: Marcia A Blackman
• 金额: $ 38.54万
• 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/8185622
• 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. PUBLIC HEALTH RELEVANCE: The ability to respond to infection or vaccination decreases dramatically with age. Elderly individuals are significantly more susceptible to infections than the young, but, unfortunately, the elderly are also more difficult to vaccinate. Therefore, it is essential that we understand the defects in immunity of the aged so that we can develop vaccine strategies that can overcome these defects. The studies proposed will use a mouse model to determine the mechanisms underlying decreased immunity of the elderly, an essential first step in the design of better vaccines.

描述（由申请方提供）：免疫功能随年龄增长而下降，导致老年人对感染的易感性增加，对疫苗的反应受损。目前建议的一个关键重点是使用流感病毒感染的良好表征的小鼠模型，以确定老年人对新感染和疫苗接种的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战略至关重要。对新遇到的抗原产生T细胞应答和对疫苗接种应答的能力取决于T细胞多样性库的维持。我们之前已经表明，CD8 T细胞之间的库多样性存在与年龄相关的减少，这对流感病毒的原发性和保护性免疫具有深远的影响。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性记忆细胞对新感染的反应做出更大贡献，这将导致随机反应，通常亲和力较低，可能是有害的或病理性的。为了支持这一点，我们有初步的数据表明，偶然的交叉反应记忆细胞从流感病毒抗原表位的流感病毒首次实验的老年小鼠可以响应，在目标1中，我们将确定交叉反应记忆的贡献，以响应新的感染，并评估细胞免疫的影响。与衰老相关的另外两个充分表征的缺陷是CD4 T细胞功能受损和产生较差的CD8 T细胞记忆。然而，老化的CD4 T细胞对有缺陷的CD8记忆的发展的贡献是衰老研究中的一个未充分研究的领域，并将在该提案的目标2中进行审查。总之，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治疗和疫苗的目标至关重要。 公共卫生相关性：随着年龄的增长，对感染或疫苗接种的反应能力急剧下降。老年人比年轻人更容易感染，但不幸的是，老年人也更难以接种疫苗。因此，我们必须了解老年人的免疫缺陷，以便我们可以开发可以克服这些缺陷的疫苗策略。这项研究将使用小鼠模型来确定老年人免疫力下降的机制，这是设计更好疫苗的重要第一步。