Impact of aging on the T cell repertoire and cellular immunity to influenza virus

衰老对 T 细胞库和流感病毒细胞免疫的影响

• 批准号: 7581328
• 负责人: Marcia A Blackman
• 金额: $ 36.49万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2009-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7581328
• 关键词: Address; Age; Aging; Antigens; Avidity; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8B1 gene; Cause of Death; Cell Aging; Cells; Cellular Immunity; Clonal Expansion; Data; Development; Elderly; Epitopes; Frequencies; Generations; Hospitalization; Human; Immune; Immune system; Immunity; Immunodominant Epitopes; Individual; Infection; Maintenance; Mediating; Memory; Modeling; Monitor; Mus; Play; Population; Predisposition; Relative (related person); Role; Seminal; T memory cell; T-Cell Antigen Receptor Specificity; T-Lymphocyte; T-Lymphocyte Epitopes; T-Lymphocyte Subsets; Vaccinated; Vaccination; Vaccines; Viral; Virus Diseases; age effect; aged; cell age; constriction; immune function; influenzavirus; mouse model; pathogen; public health relevance; research study; respiratory infection virus; response; vaccination strategy

DESCRIPTION (provided by applicant): The capacity of the immune system to respond to pathogen challenge or vaccination decreases dramatically with age. Since the initiation of T cell responses to newly encountered antigens during infection or vaccination is dependent on a diverse repertoire of T cells, we hypothesize that impaired immune function in the aged is due, in part, to declining T cell diversity. To address this hypothesis, we are exploiting a well- developed mouse model of influenza virus to assess the impact of declining immune function on the effective response to pathogen challenge. Our preliminary data confirm that there is an age-associated reduction in repertoire diversity among naove CD8 T cells. In addition, we have made the seminal observation that there is a preferential loss of the ability of aged mice to respond to specific influenza virus epitopes and that this correlates with a low precursor frequency of T cells for these epitopes. This results in the development of "holes in the repertoire" following de novo influenza virus infection, which correlated with impaired protective immunity assessed by heterosubtypic challenge. Clearly, these findings have profound implications for the development of rational vaccination strategies for the elderly. However, the extent to which reduced repertoire diversity directly impacts viral clearance is not known. We also don't know whether there are similar age-associated perturbations of the CD4 repertoire, and to what extent this impacts CD4 responses, as well as the generation and maintenance of functional CD8 memory. The Specific Aims are directed toward answering these questions. The proposed studies will advance the field by enhancing our understanding of the impact of aging on the repertoire and reactivity of CD4 and CD8 T cells. The data generated will have important implications for the development of effective vaccines for the elderly. PUBLIC HEALTH RELEVANCE: The capacity of the immune system to respond to pathogen challenge or vaccination decreases dramatically as we age. Elderly individuals are significantly more susceptible to infections than the young and notoriously difficult to successfully vaccinate. Consequently, respiratory virus infections, such as those mediated by influenza virus, are a major cause of death and hospitalization in the elderly. The studies proposed in the current application will determine the mechanisms underlying decreased immune responsiveness in a mouse model of influenza virus infection. The data generated will provide essential information for the development of new vaccination strategies suitable for aged individuals.

描述（由申请人提供）：免疫系统对病原体攻击或疫苗接种的反应能力随年龄增长而显著下降。由于在感染或疫苗接种过程中T细胞对新遇到的抗原的应答的启动依赖于T细胞的多样性，我们假设老年人的免疫功能受损部分是由于T细胞多样性下降。为了解决这一假设，我们正在利用一个完善的流感病毒小鼠模型来评估免疫功能下降对病原体攻击的有效反应的影响。我们的初步数据证实，在新生CD8 T细胞中存在与年龄相关的库多样性减少。此外，我们还进行了开创性的观察，即老年小鼠对特定流感病毒表位的反应能力优先丧失，这与这些表位的T细胞前体频率低相关。这导致在新发流感病毒感染后出现“库中的孔”，这与通过异亚型攻击评估的保护性免疫受损相关。显然，这些发现对制定老年人合理的疫苗接种策略具有深远的意义。然而，库多样性减少直接影响病毒清除的程度尚不清楚。我们也不知道是否有类似的年龄相关的干扰CD4库，以及在何种程度上影响CD4的反应，以及功能性CD8记忆的产生和维持。具体目标是为了回答这些问题。拟议的研究将通过增强我们对衰老对CD4和CD8 T细胞的库和反应性的影响的理解来推进该领域。所产生的数据将对开发针对老年人的有效疫苗具有重要意义。公共卫生相关性：随着年龄的增长，免疫系统对病原体挑战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，并且众所周知很难成功接种疫苗。因此，呼吸道病毒感染，如流感病毒介导的感染，是老年人死亡和住院的主要原因。本申请中提出的研究将确定流感病毒感染小鼠模型中免疫应答降低的潜在机制。所产生的数据将为制定适合老年人的新疫苗接种策略提供重要信息。