Cellular and molecular programming of lung resident T cell memory

项目总结 流感病毒是全球主要的健康负担，导致数十亿美元的医疗费用和高达 每年有60万人死亡。因此，肺部疫苗学的一个主要挑战是开发一种方法， 为肺部提供持久持久的免疫力。季节性流感感染主要是由 抗原转移以避免已建立的抗体反应，限制了当前流感疫苗的效力 旨在产生对血凝素蛋白的体液免疫。解决此问题的一种方法是 开发旨在促进流感特异性肺部驻留T细胞产生的疫苗 记忆。在动物模型和人类研究中，记忆T细胞已被证明可以显著减少病毒 流感挑战后的病毒载量，导致病毒更快清除，传播减少，病情较轻或亚 临床症状。已发现肺组织驻留记忆T细胞(肺TRM)对此至关重要 对流感的保护性细胞反应，但肺TRM数量随着时间的推移逐渐下降。尽管如此 对于肺免疫的重要性，我们仍然只对细胞和分子有基本的了解 控制它们产生和长期维护的机制，我们也没有确定最优的 诱导持久肺TRM的疫苗接种策略。此外，对独特的微环境的影响 肺间质和肺气道对TRM生物学的影响知之甚少。这项提案旨在开发一种 肺TRM生物学计划集中在三个相关主题：(I)研究 能够在感染和接种疫苗后产生的TRM；(Ii)定义细胞和组织固有的 驱动肺TRM逐渐丧失的机制和测试新疫苗策略的能力 改善肺TRM寿命；以及(Iii)确定流感的转录和表观遗传编程- 使用人肺样本的生物储存库，在整体和单细胞水平上进行特定的肺TRM。总目标 这个项目的主要目的是了解推动人类免疫缺陷病毒最初产生和随后衰退的机制。 来自肺间质和呼吸道的流感特异性TRM。在这项研究中获得的知识将为 深入了解调节肺TRM生物学的机制，以更好地指导未来的疫苗设计 对抗呼吸道病原体。

PROJECT SUMMARY Influenza virus is a major health burden worldwide, resulting in billions of dollars in medical costs and up to 600,00 deaths annually. Thus, a major challenge of pulmonary vaccinology is to develop an approach that will provide long-lasting and durable immunity in the lung. Seasonal influenza infection is driven largely by antigenic shift to avoid established antibody responses, limiting the efficacy of current influenza vaccinations designed to generate humoral immunity to the hemagglutinin protein. One approach to this problem is the development of vaccines designed to promote the generation of influenza-specific, lung-resident T cell memory. In animal models and human studies, memory T cells have been shown to significantly reduce viral loads after influenza challenge, leading to faster viral clearance, decreased transmission, and milder or sub- clinical symptoms. Lung tissue-resident memory T cells (lung TRM) have been found to be critical for this protective cellular response to influenza, but lung TRM numbers gradually decline over time. Despite thie importance for pulmonary immunity, we still have only a basic understanding of the cellular and molecular mechanisms that control their generation and long-term maintenance, nor have we identified the optimal vaccination strategies to induce durable lung TRM. Furthermore, the influence on unique microenvironments of the lung interstitium and lung airways on TRM biology is poorly understood. This proposal seeks to develop a program in lung TRM biology centered on three related themes: (i) investigating the molecular programming of TRM that enables their generation following infection and vaccination; (ii) defining the cell- and tissue-intrinsic mechanisms that drive the gradual loss of lung TRM and testing the ability of novel vaccinations strategies to improve lung TRM longevity; and (iii) determining the transcriptional and epigenetic programming of influenza- specific lung TRM at the bulk and single cell level using a biorepository of human lung samples. The overall goal of this project is to understand the mechanisms driving the initial generation and subsequent decline of influenza-specific TRM from the lung interstitium and airways. The knowledge gained in this study will provide a deep understanding of the mechanisms that regulate lung TRM biology to better inform future vaccine design against respiratory pathogens.