The generation and protective function of lung tissue resident memory T cells following SARS-CoV-2 infection or vaccination

项目总结/摘要 2019冠状病毒病（COVID-19），由严重急性呼吸道综合征冠状病毒2（SARS- CoV-2）爆发为全球大流行，造成重大生命损失，明显的经济影响， 长期的医疗影响仍在描述中。尽管提供了令人印象深刻的保护， 目前的SARS-CoV-2疫苗主要通过抗体中和病毒来介导， 抗体随着时间的推移而减弱，并且出现了对这些抗体不太敏感的新的病毒变体。 一个主要的问题是记忆T细胞是否在SARS-CoV-2感染期间提供更持久的保护。 先前的研究表明，从2003年SARS冠状病毒感染中恢复的人表现出SARS冠状病毒， 特异性记忆性CD 8 + T细胞反应在外周血中长达11年，病毒特异性抗体没有 在6年时可检测到，并且与MERS-CoV肽没有交叉反应性1，2。对于目前的大流行， 然而，我们开始了解血液中SARS-Cov 2感染后形成的记忆T细胞和B细胞的类型， 我们不知道这些反应的寿命。更重要的是，我们对肺动脉 记忆T和B细胞在SARS-CoV-2感染后在肺部形成， 从其他病毒中学习，这些可能是上级记忆细胞所需的最具保护性的记忆细胞， 术语对再感染的免疫力。 在Teijaro，Kaech和Farber实验室之间的这项合作计划中，我们将世界各地的人聚集在一起- 在抗病毒免疫和肺部发病机制，免疫记忆和人类免疫学方面的一流专业知识 研究肺驻留TRM细胞在SARS-CoV-2中的发育和保护作用。在目标1中，我们 研究SARS-CoV-2 TRM在hACE 2转基因小鼠肺中发育的基本原理， 通过Tgfbr 2的遗传干扰来确定TRM是否是长期免疫所必需的， T细胞中的Smad 4，TRM分化所需的差异3，以及循环中Smad 4的消耗。 记忆细胞在目标2中，我们将检查肺TRM细胞是否有助于mRNA提供的保护。 疫苗，以更好地了解记忆T细胞在介导对SARS-CoV-2的保护中的作用， 值得关注的变异体（VOC）。最后，在目标3中，我们扩展并补充了我们在小鼠中的研究。 Farber的人类供体库，以评估SARS-CoV-2感染后人类记忆的形成， 预防针我们希望回答SARS后形成哪种记忆T细胞的基本问题- CoV-2感染，并赋予对这种病毒和VOC的长期保护性免疫。这些研究将 提供了与SARS-CoV后形成的免疫记忆质量相关的关键信息， 2感染小鼠和人类，并将用于指导当前和未来的疫苗开发。

Project Summary/Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), has exploded into a global pandemic causing significant loss of life, pronounced economic impact and significant long-term medical impacts which are still being characterized. Despite impressive protection afforded by the current SARS-CoV-2 vaccines which are primarily mediated by antibody neutralization of virus, these antibodies wane over time and new viral variants have emerged that are less susceptible toby these antibodies. A major question is whether memory T cells afford more long-lasting protection during SARS-CoV-2 infection. Prior studies showed that people who recovered from SARS-CoV infection from 2003 exhibited SARS-CoV- specific memory CD8+ T cell responses in peripheral blood for up to 11 years, virus-specific antibodies were not detectable at 6 years, and there was no cross-reactivity with MERS-CoV peptide1,2. For the current pandemic, we are starting to learn what types of memory T and B cells form after SARS-Cov2 infection in the blood, however we have no idea the longevity of these responses. More importantly, we know very little about the pulmonary memory T and B cells that form in the lung after SARS-CoV-2 infection and, based on what has been learned from other viruses, these may be the most protective memory cells needed for superior long- term immunity to reinfection. In this collaborative proposal between the Teijaro, Kaech and Farber labs, we bring together world- class expertise in anti-viral immunity and lung pathogenesis, immunological memory and human immunology to study the development and protective role of lung-resident TRM cells in SARS-CoV-2. In Aim 1, we will study the fundamentals of SARS-CoV-2 TRM development in the lungs of hACE2-transgenic mice and determine whether TRM are required for long- term immunity, through genetic perturbations of Tgfbr2 and Smad4 in T cells, which are differentially required for TRM differentiation3, and the depletion of circulating memory cells. In Aim 2, we will examine if lung TRM cells contribute to the protection afforded by mRNA vaccines to better understand the role, if any, of memory T cells in mediating protection to SARS-CoV-2 and notable variants of concern (VOC). Lastly, in Aim 3, we extend and complement our studies in mice to Dr. Farber’s human donor repository to assess human memory formation following SARS-CoV-2 infection and vaccination. We hope to answer the basic question of which types of memory T cells form after SARS- CoV-2 infection and confer long-term protective immunity to this virus and VOCs. These studies will provide critical information related to the quality of immunological memory that forms after SARS-CoV- 2 infection in mice and humans and will serve to guide current and future vaccine development.