Antiviral lung resident memory T cell maintenance and reinvigoration

项目摘要 季节性流感A（IAV）和其他空气传播的病毒病原体，如SARS-CoV-2，代表了一个重大的 对全球公共卫生造成负担。虽然杀菌免疫可以通过中和抗体来实现， 季节性抗原漂移允许病毒逃避体液免疫，这就需要每年重新配制 季节性流感疫苗。以前已经表明，交叉反应性CD 8 + T细胞可以提供 对IAV的异亚型非绝育免疫。然而，这种交叉保护在欧洲相对短暂， 单一抗原暴露的情况下。我们的实验室已经表明，肺组织驻留记忆T细胞（肺Trm） 有助于该菌株超越交叉保护，并且IAV特异性Trm数量的减少强烈地影响了该菌株的免疫应答。 与IAV交叉保护的丧失有关。重要的是，我们发现，多次暴露于相同的环境中， IAV抗原（加强）可以延长这些肺Trm群体的寿命，并且因此，提供延长的免疫应答。 异型免疫关于为什么肺Trm细胞如此短，仍然存在大量的知识缺口 当它们显然对保护很重要的时候。解决这个问题仍然是理性的关键一步。 设计通用流感疫苗。我们的长期目标是了解 减少肺Trm细胞，并利用这一信息，以帮助发展广泛的保护性 流感疫苗。我们将通过以下具体目标实现这一长期目标： 目的1：确定延长肺寿命和肺功能的分子T细胞内在因子 多种抗原暴露后的Trm。 目的2：确定最佳的初免和加强疫苗接种策略，以最大限度地提高Trm的产生，重新接种， 活力和功能。

PROJECT SUMMARY Seasonal influenza A (IAV) and other airborne viral pathogens such as SARS-CoV-2 represent a substantial burden on global public health. While sterilizing immunity can be attained through neutralizing antibodies, seasonal antigenic drift permits viral evasion of humoral immunity, which necessitates annual reformulation of the seasonal influenza vaccine. It has previously been shown, that cross-reactive CD8+ T cells can provide heterosubtypic non-sterilizing immunity to IAV. However, this cross-protection is relatively short-lived in the context of a singular antigen exposure. Our lab has shown that lung tissue resident memory T cells (lung Trm) contribute to this strain transcending cross-protection and that the waning in numbers of IAV-specific Trm strongly correlate with this loss of IAV cross-protection. Importantly, we have found that multiple exposures to the same IAV antigens (boosting) can extend the longevity of these lung Trm populations, and as a result, provide extended heterosubtypic immunity. There still exists a substantial knowledge gap regarding why lung Trm cells are so short lived when they are clearly important for protection. Addressing this question remains a critical step in the rational design of universal influenza vaccines. Our long-term goal is to understand the biology that underlies the waning of lung Trm cells and to harness this information to aid in the development of broadly protective influenza vaccines. We will address this long-term goal with the following specific aims: Aim 1: Determine the molecular T cell intrinsic factors that permit extended longevity and functionality of lung Trm following multiple antigen exposures. Aim 2: Define the optimal priming and boosting vaccination strategies to maximize Trm generation, re- invigoration, and function.