Aging and Immunity to Infection

描述(申请人提供)：传染病，如流感，在老年人口中导致高发病率和死亡率。此外，疫苗对老年人口的效力也大大降低，使他们更容易受到感染。虽然众所周知，对流感感染的获得性免疫反应和免疫随着年龄的增长而下降，但与年龄相关的特定T细胞功能变化的影响仍有待阐明。在人类群体中定义随着年龄增长的免疫反应的潜在缺陷是极其困难的。幸运的是，小鼠模型允许我们精确地检查免疫系统中与年龄相关的变化，并确定这些变化对特定病原体的反应的影响。因此，该计划的重点是评估与年龄相关的T细胞功能变化的发展，确定导致这些缺陷的机制，并确定它们是否也与人类免疫系统的下降有关。项目1“衰老对CD4流感免疫的影响”将研究年龄对CD4T细胞初级反应和记忆反应的影响，以及这一影响是否可以增强。项目2“老化对T滤泡辅助器(TFH)细胞的影响”将集中于研究与年龄相关的CD4T细胞辅助器功能变化对体液反应的作用，以及这如何影响疫苗接种后保护性抗体的产生。项目3“年龄对CD8+T细胞对呼吸道感染免疫的影响”将研究CDS T细胞记忆的生成和功能，随着年龄的增长，CDS T细胞的记忆能力显著降低，这可能是由于记忆T细胞亚群的稳态改变。项目4“衰老对T细胞库和对流感病毒的细胞免疫的影响”将研究与年龄相关的CD4和CDS T细胞库的变化，以及这些变化如何影响对流感感染的反应能力。所产生的知识将使今后制定战略以克服这些缺陷并提高老年人的疫苗效力。项目5“衰老对接种流感疫苗的T细胞反应的影响”将把在小鼠模型上的发现转化为对不同年龄段接种疫苗的成年人的人类幼稚和记忆性T细胞的研究。

DESCRIPTION (provided by applicant): Infectious diseases, such as influenza, lead to high morbidity and mortality in elderly populations. In addition, the efficacy of vaccines is also significantly reduced for elderly populations, leaving them much more vulnerable to infection. While it is well known that the adaptive immune response to influenza infection and immunization declines with aging, the impact of specific age-related changes in T cell function remains to be elucidated. Defining the underlying defects in the immune response with aging in human populations is extremely difficult. Fortunately, mouse models allow us to precisely examine age-related changes in the immune system and determine the effect of these changes on a response to a particular pathogen. Thus, the key focus of this program is to assess the development of age-related changes in T cell function, define the mechanisms responsible for these defects and determine if they are also involved in declines in the human immune system. Project 1 "Impact of aging on CD4 immunity to flu" will examine the impact of age on CD4 T cell primary and memory responses and if this can be enhanced. Project 2 " Influence of aging on T follicular helper (Tfh) cells" will focus on examining the role of age-related changes in CD4 T cel cognate helper function for humoral responses and how this impacts the production of protective antibodies following vaccination. Project 3 "Impact of age on CD8+ T cell immunity to respiratory infection " will examine CDS T cell memory generation and function, which is dramatically reduced with aging possibly due to changes in homeostasis of memory T cell subsets. Project 4 "Impact of aging on the T cell repertoire and cellular immunity to influenza virus" will examine age- related changes in CD4 and CDS T cell repertoire and how these influence the ability to respond to influenza infection. The knowledge generated will allow the future development of strategies to overcome these defects and enhance vaccine efficacy for the elderly. Project 5 "Impact of aging on T cell responses to influenza vaccination" will translat findings in mouse models to studies in human naive and memory T cells from different age groups of vaccinated adults.