Memory CD8 T cell localization and protection from influenza

记忆 CD8 T 细胞定位和流感保护

• 批准号: 10077814
• 负责人: VLADIMIR P BADOVINAC
• 金额: $ 46.03万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077814
• 关键词: Address; Antigens; Biology; C-Type Lectins; CD8-Positive T-Lymphocytes; Cells; Cellular Immunology; Cytoprotection; Data; Development; Disease; Exhibits; Female; Generations; Goals; Health; Human; Immunity; Infection; Influenza; Influenza vaccination; Integrins; Intestines; Knowledge; Laboratories; Longevity; Lung; Lymphoid; Lymphoid Tissue; Maintenance; Mediastinal lymph node group; Memory; Metabolic; Molecular; Mus; Paper; Parabiosis; Play; Population; Principal Investigator; Public Health; Reporting; Resistance; Role; Skin; Structure of parenchyma of lung; Symptoms; T-Lymphocyte; Time; Tissues; Transcend; Universal Coverage; Vaccines; Viral; Viral Proteins; Work; genetic approach; imaging approach; improved; influenza infection; insight; mouse model; neutralizing antibody; pandemic disease; programs; reproductive tract; seasonal influenza; trait; transcriptome; two-photon; universal influenza vaccine

Influenza infection is a recurring public health burden and our current strategies of seasonal influenza vaccination provide suboptimal protection. Thus, it is critical to provide basic, mechanistic insights into the possibility of universal influenza vaccines and much work is devoted to strategies to induce broadly neutralizing antibodies. However, in the absence of neutralizing antibodies, the presence of IAV-specific memory CD8 T cells targeting conserved viral proteins such as NP or M2, which are maintained systemically as well as in the lung correlate with control of viral titers and reduction of disease symptoms in humans. Mouse models suggest it is the lung resident memory CD8 T cells (Trm) that enable swift and robust protection against IAV infection. Thus, establishing a robust long-term Trm population in the lung may be an important goal for an IAV vaccine with broad coverage. Recent evidence from our laboratories shows that repetitive encounter with influenza infection to generate quaternary (4M) memory in the lung profoundly improves the durability of lung Trm and heterosubtypic immunity compared to primary (1M) memory Trm. Our long-term goal is to understand the biology of IAV-induced Trm and how these cells can be manipulated to enhance immunity to aid in development of universal influenza vaccines. We will address this long-term goal with the following specific aims: Specific Aim 1. Determine the mechanisms underlying improved durability of 4M vs 1M IAV-specific lung Trm Specific Aim 2. Determine if IAV-specific 4M lung Trm provide better per cell protection than 1M lung Trm Specific Aim 3. Dissect the role of 4M vs 1M IAV-specific CD69+CD103+ LN populations

流感感染是一种反复出现的公共卫生负担，我们目前的季节性流感策略 疫苗接种提供次优保护。因此，提供基本的、机械的见解至关重要。 通用流感疫苗的可能性，并且大量工作致力于制定广泛诱导流感疫苗的策略 中和抗体。然而，在缺乏中和抗体的情况下，IAV 特异性抗体的存在 记忆 CD8 T 细胞靶向保守的病毒蛋白，如 NP 或 M2，这些蛋白被维持 全身以及肺部与病毒滴度的控制和疾病症状的减少相关 人类。小鼠模型表明，肺内常驻记忆 CD8 T 细胞 (Trm) 能够快速且有效地 针对 IAV 感染提供强有力的保护。因此，在肺中建立强大的长期 Trm 群体可能 成为具有广泛覆盖范围的 IAV 疫苗的一个重要目标。我们实验室的最新证据表明 反复遭遇流感感染，在肺部产生深刻的四级（4M）记忆 与初级 (1M) 记忆 Trm 相比，提高了肺 Trm 和异亚型免疫的持久性。 我们的长期目标是了解 IAV 诱导的 Trm 的生物学特性以及这些细胞如何 操纵以增强免疫力，以帮助开发通用流感疫苗。我们将解决 这一长期目标具有以下具体目标： 具体目标 1. 确定 4M 与 1M IAV 特异性肺耐久性改善的机制 特姆 具体目标 2. 确定 IAV 特异性 4M 肺 Trm 是否比 1M 肺 Trm 提供更好的每细胞保护 具体目标 3. 剖析 4M 与 1M IAV 特异性 CD69+CD103+ LN 群体的作用