Cellular and molecular programming of lung resident T cell memory

项目摘要 流感病毒是世界范围内的主要健康负担，导致数十亿美元的医疗费用， 每年有60万人死亡。因此，肺疫苗学的主要挑战是开发一种方法， 在肺部提供持久的免疫力。季节性流感感染主要是由 抗原转移，以避免建立抗体反应，限制了目前流感疫苗的效力 旨在产生对血凝素蛋白的体液免疫。解决这个问题的一种方法是 开发旨在促进流感特异性肺驻留T细胞生成的疫苗 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感染。 流感病毒攻击后的负荷，导致更快的病毒清除，减少传播，和温和或亚 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 肺TRM的数量随着时间的推移逐渐下降。尽管如此， 虽然肺免疫的重要性，我们仍然只有一个基本的了解细胞和分子 控制其产生和长期维持的机制，我们也没有确定最佳的 疫苗接种策略，以诱导持久的肺TRM。此外，对独特的微环境的影响， 对TRM生物学上的肺结节和肺气道了解甚少。该建议旨在制定一项 在肺TRM生物学程序集中在三个相关的主题：（一）调查的分子编程 TRM，使它们能够在感染和接种疫苗后产生;（ii）定义细胞和组织内在的 驱动肺TRM逐渐丧失的机制，并测试新疫苗接种策略的能力， 改善肺TRM寿命;和（iii）确定流感病毒的转录和表观遗传编程- 使用人肺样品的生物储存库在本体和单细胞水平上测定特异性肺TRM。总目标 这个项目的目的是了解驱动初始生成和随后下降的机制， 流感特异性TRM来自肺结核和气道。本研究中获得的知识将提供 深入了解调节肺TRM生物学的机制，以更好地为未来的疫苗设计提供信息 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.