Effects of aging on the T follicular helper response to influenza vaccine

描述(申请人提供)：在过去的60年里，流感疫苗接种一直用于预防流感感染。然而，一些人对疫苗接种没有反应，随着年龄的增长，疫苗接种的频率更高。不幸的是，这一人群是流感发病率和死亡率最高的人群。对流感的保护来自于B细胞产生的中和抗体，这需要T滤泡助手(TFH)CD4T细胞的帮助。我们已经发现循环中的转铁蛋白(CTfh)降低了老年人的B细胞帮助能力，并且确实 与年轻人相比，接种流感疫苗的反应不是很好。我们假设，cTfh功能异常和对疫苗的反应预测了疫苗接种的流感特异性抗体反应与年龄相关的减少。这些研究将阐明老年人cTfh功能能力下降的原因。这些研究将为未来合理的疫苗设计工作提供信息。 并提高我们预测疫苗无反应的能力。要解决的具体目标包括： *目标1：信号通路中的细胞内在变化是否解释了cTfh功能障碍与年龄的关系？我们发现与年轻人相比，老年人cTfh对细胞因子的反应性降低。我们推测，其他信号通路可能会受到影响。我们将评估衰老对STAT信号的影响，老年人cTfh与B细胞直接接触的能力，以及药物是否可以改善cTfh的功能。 *目标2：T滤泡调节细胞是否对疫苗应答有年龄相关的影响？我们已经鉴定出T滤泡调节细胞(CTfr)可以抑制B细胞帮助cTfh的能力。我们将询问cTfr的抑制作用，并评估是否存在cTfr对疫苗的反应，这有助于提高抗体反应的预测。 *目标3：老年人在接种疫苗后是否会产生不那么多样化的TFH曲目？许多研究已经发现，随着年龄的增长，T细胞的谱系会变窄。在这里，我们将调查基于T细胞受体的cTfh谱系，以确定年轻人和老年人谱系的广度是否存在差异，确定个体之间共同的公共克隆型，并评估血统关系。结合对疫苗抗体反应的了解，这些数据将确定缩小的TFH谱系是否与疫苗抗体反应相关。 Wherry博士是我在宾夕法尼亚大学的主要导师，有强大的机构支持，我一直在研究T细胞对疫苗接种的反应，重点是Tfh亚群，在老龄化的背景下。我组建了一个指导委员会，概述了生物统计学和计算方法方面的教学计划，并确定了一些里程碑，这些里程碑将作为我作为研究人类免疫学中T细胞反应的独立研究员的职业生涯的基础。

DESCRIPTION (provided by applicant): For the past 60 years, influenza vaccination has been used to prevent influenza infection. However, some individuals do not respond to vaccination, which occurs more frequently with age. Unfortunately, this population is at highest risk for morbidity and mortality from influenza. Protection from influenza is derived from neutralizing antibody production by B cells, which require help from T follicular helper (Tfh) CD4 T cells. We have identified circulating Tfh (cTfh) that have reduced B cell help ability in the elderly and did not respond as well to influenza vaccination compared to young. We hypothesize that abnormal cTfh function and responses to vaccination predict age-related reduction in influenza-specific antibody responses to vaccination. These studies will clarify the etiology behind reduced cTfh functional ability in the elderly. These studies will inform future rational vaccine design efforts and improve our ability to predict vaccine nonresponses. The specific aims to be addressed are: * Aim 1: Do cell-intrinsic changes in signaling pathways explain cTfh dysfunction with aging? We have identified reduced responsiveness to cytokines in cTfh from the elderly compared to young. We hypothesize that other signaling pathways may be compromised. We will assess the effect of aging on STAT signaling, the ability of cTfh from the elderly to effectively maintain direct contact with B cells, and whether pharmacological agents can improve cTfh function. * Aim 2: Do T follicular regulatory cells have an age-related effect on the vaccine response? We have identified T follicular regulatory cells (cTfr) which suppress B cell help ability of cTfh. We will interrogate the suppressive effects of cTfr and assess whether there is a cTfr response to vaccination that helps improve prediction of antibody responses. * Aim 3: Do the elderly generate a less diverse Tfh repertoire after vaccination? Many studies have identified narrowed repertoire in T cells with aging. Here, we will investigate the repertoire in cTfh based on the T cell receptor to establish whether there is a difference in breadth of repertoire in the young and elderly, identify public clonotypes common between individuals, and assess lineage relationships. Combined with knowledge of the antibody response to vaccination, these data will identify if narrowed Tfh repertoire can correlate with antibody responses to vaccination. With Dr. Wherry as my primary mentor at UPenn and strong institutional support, I have been investigating T cell responses to vaccination, with focus on the Tfh subset, in the setting of aging. I have assembled a mentorship committee, outlined a didactic plan in biostatistics and computational methods, and identified milestones that will serve as the basis for my career as an independent investigator studying T cell responses in human immunology.