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

肺组织驻留记忆CD8 T细胞长期维持的机制

• 批准号: 10531128
• 负责人: Jenna L. Lobby
• 金额: $ 4.68万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531128
• 关键词: Acute respiratory infection; Address; Adenovirus Vector; Adenoviruses; Antibody Response; Antigens; Biology; Blood Circulation; Bronchoalveolar Lavage; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Immunity; Data; Environment; Epitopes; Future; Generations; Goals; Health; Human; Immune; Immunity; Immunization; Immunize; Infection; Inflammation; Influenza; Knowledge; Longevity; Lung; Lymphoid; Maintenance; Mediating; Mediator of activation protein; Memory; Molecular; Morbidity - disease rate; Mus; Mycobacterium tuberculosis; Nucleoproteins; Peripheral; Population; Recombinants; Respiratory Tract Infections; Role; Severity of illness; Site; Skin; Source; Stable Populations; Structure of parenchyma of lung; T cell response; T memory cell; T-Lymphocyte; Time; Tissues; Vaccination; Vaccine Design; Vaccines; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Virus Replication; base; cell type; cross reactivity; design; directed differentiation; improved; influenza infection; influenza virus strain; influenza virus vaccine; influenzavirus; insight; mortality; novel; pathogen; pathogenic virus; prevent; recombinant adenovirus; reproductive tract; respiratory; respiratory challenge; respiratory pathogen; response; vaccination strategy; vaccine strategy; vector

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.

项目摘要/摘要： 尽管有季节性疫苗的可用性，但流感病毒仍然是人类健康的重要负担， 每年都在全球感染数百万美元。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，这使病毒能够逃避已建立的抗体反应。因此，开发新的 引起可以识别多样化流感菌株的广泛保护反应的策略很棒 重要性。一种潜在的策略是开发基于T细胞的疫苗，该疫苗可以识别保守的内部疫苗 表位并提供许多流感菌株的保护性免疫。虽然细胞免疫不能 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 组织居住的记忆CD8 T细胞（CD8 TRM）是确定的记忆T细胞的关键子集 原发性呼吸道感染后，并保持在肺组织中的位置，它们提供了快速 防止随后的呼吸挑战。但是，而CD8 TRM在其他屏障中鉴定 皮肤和肠道等组织已被证明保持稳定并提供持久的保护，CD8 随着时间的流逝，肺中的TRM逐渐下降。重要的是，我们的初步研究表明肺CD8的丧失 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 了解管理肺中组织居住记忆CD8 T细胞维持的机制 仍然有限。我们的小组还确定了几种策略，包括重组的免疫 腺病毒载体和重组流感病毒的质量促进方法，导致长期 小鼠肺中流感特异性CD8 TRM的术语维持。我们的主要目标是确定 遵循这些的CD8肺TRM寿命增强的机制 感染/免疫策略。这项研究的结果将为细胞介导的流感的未来设计提供信息 疫苗通过对肺部TRM的维持有价值的洞察力，从而提供耐久性的耐用性 对呼吸道病原体的免疫力。