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: 10534144
• 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/10534144
• 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; Membrane; Memory; Metabolic; Molecular; Mus; Paper; Parabiosis; Play; Population; Principal Investigator; Public Health; Recurrence; 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; influenza virus vaccine; insight; mouse model; neutralizing antibody; pandemic potential; 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

流感感染是一个经常性的公共卫生负担，我们目前的季节性流感策略 接种疫苗提供次优保护。因此，至关重要的是要提供基本的，机械的见解， 通用流感疫苗的可能性，许多工作致力于广泛诱导 中和抗体然而，在缺乏中和抗体的情况下， 靶向保守病毒蛋白如NP或M2的记忆性CD8 T细胞， 全身性以及肺中的感染与控制病毒滴度和减少疾病症状相关， 人类小鼠模型表明，肺驻留记忆性CD8 T细胞（Trm）能够迅速和有效地抑制CD8 T细胞。 对IAV感染的强大保护。因此，在肺中建立稳健的长期Trm群体可以 是广泛覆盖的IAV疫苗的重要目标。我们实验室的最新证据表明 反复接触流感感染在肺部产生四元（4M）记忆， 与初级（1M）记忆Trm相比，改善了肺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，以及这些细胞如何能够在体外被激活。 操纵以增强免疫力，以帮助开发通用流感疫苗。我们将解决 这一长期目标的具体目标如下： 具体目标1.确定4M与1M IAV特异性肺的耐久性改善的潜在机制 TRM 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4 M与1 M IAV特异性CD 69 + CD 103 + LN群体的作用