Mechanisms of long-term maintenance of lung tissue-resident memory CD8 T cells

项目摘要/摘要： 尽管有季节性疫苗可用，流感病毒仍然是人类健康的关键负担， 每年感染全球数百万人。当前流感疫苗策略的有限效力在很大程度上是 由于抗原转移，允许病毒逃避既定的抗体反应。因此，开发新的 激发能够识别不同流感病毒株的广泛保护性反应的策略是非常重要的 重要性。一种潜在的策略是开发一种基于T细胞的疫苗，它可以识别保守的内部 并对多种流感毒株提供保护性免疫。而细胞免疫则不能 预防流感感染，预先存在的抗病毒T细胞可以限制病毒复制和疾病严重程度。肺 组织驻留记忆性CD8 T细胞(CD8 TRM)是已建立的记忆性T细胞的关键亚群 在原发呼吸道感染后，并停留在肺组织内，在那里它们提供快速 针对随后的呼吸挑战的保护。然而，尽管在其他屏障中发现了CD8 TRM 皮肤和肠道等组织被证明保持稳定并提供持久的保护，CD8 随着时间的推移，肺内TRM逐渐下降。重要的是，我们的初步研究表明，肺CD8的丢失 TRM与包括流感在内的呼吸道感染的细胞免疫力下降有关。目前，我们的 对肺中组织驻留记忆CD8 T细胞维持机制的认识 仍然是有限的。我们小组还确定了几种策略，包括用重组人免疫 腺病毒载体和重组流感病毒的初始增强方法，导致长时间的- 小鼠肺内流感特异性CD8TRM的长期维持。我们的主要目标是确定 CD8肺TRM寿命延长的机制观察如下 感染/免疫策略。这项研究的结果将为未来细胞介导型流感的设计提供参考。 疫苗通过提供有价值的洞察力来维持肺TRM，从而了解细胞的持久性 对呼吸道病原体具有免疫力。

Project Summary/Abstract: Despite the availability of a seasonal vaccine, influenza virus remains a critical burden to human health, infecting millions worldwide every year. The limited efficacy of current influenza vaccine strategies is largely due to antigenic shift, which allows the virus to evade established antibody responses. Thus, developing new strategies to elicit broadly protective responses that can recognize diverse influenza strains is of great importance. One potential strategy is to develop a T-cell based vaccine that could recognize conserved internal epitopes and provide protective immunity across many influenza strains. While cellular immunity cannot prevent influenza infection, pre-existing antiviral T cells can limit viral replication and disease severity. Lung tissue-resident memory CD8 T cells (CD8 TRM) are a critical subset of memory T cells that are established following primary respiratory infection and remain localized within the lung tissue, where they provide rapid protection against subsequent respiratory challenge. However, whereas CD8 TRM identified in other barrier tissues such as the skin and gut have been shown to remain stable and provide long-lasting protection, CD8 TRM in the lung gradually decline over time. Importantly, our preliminary studies show that the loss of lung CD8 TRM correlates with a decline in cellular immunity to respiratory infection, including influenza. Currently, our knowledge of the mechanisms governing the maintenance of tissue-resident memory CD8 T cells in the lung remains limited. Our group has also identified several strategies, including immunization with a recombinant adenovirus vector and a prime-boost approach with recombinant influenza viruses, which result in the long- term maintenance of influenza-specific CD8 TRM in the lungs of mice. Our major objective is to identify the mechanisms responsible for the enhanced longevity of CD8 lung TRM observed following these infection/immunization strategies. The results of this study will inform future design of cell-mediated influenza vaccines by providing valuable insight into the maintenance of lung TRM, and thus, the durability of cellular immunity to respiratory pathogens.