Antigen-independent activation of memory CD8 T cells during respiratory infection

呼吸道感染期间记忆 CD8 T 细胞的抗原非依赖性激活

• 批准号: 7898591
• 负责人: JACOB E KOHLMEIER
• 金额: $ 28.2万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-23 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898591
• 关键词: Accounting; Address; Air; Antigens; Antiviral Agents; CCR5 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Immunity; Cessation of life; Cytokine Signaling; Cytolysis; Data; Development; Environment; Future; Generations; Genital system; Health; Human; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Influenza; Intestines; Light; Lung; Lymphoid; Lymphoid Tissue; Mediating; Memory; Morbidity - disease rate; Mus; Organ; Peripheral; Play; Process; Production; Proteins; Public Health; Publishing; Recruitment Activity; Regulation; Resolution; Respiratory System; Respiratory Tract Infections; Respiratory tract structure; Rest; Role; STAT1 gene; STAT1 protein; Sampling; Signal Transduction; Site; Spleen; Staging; Structure of parenchyma of lung; Surface; T-Lymphocyte; Testing; Tissues; United States; Up-Regulation; Vaccine Design; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; chemokine receptor; cytokine; cytotoxicity; design; granzyme B; in vivo; insight; memory recall; mortality; parainfluenza virus; pathogen; protein expression; respiratory; respiratory infection virus; respiratory virus; response; trafficking

DESCRIPTION (provided by applicant): Project Description: The mucosal surfaces of the respiratory tract are in direct contact with the surrounding environment, and as such are a primary portal of entry for human pathogens such as influenza and parainfluenza viruses. The significant public health threat that these viruses pose has highlighted the need for the development of more efficacious vaccines designed to promote robust and long-lasting pulmonary immunity. However, our incomplete understanding of how cellular immunity contributes to protection from respiratory viruses has complicated the development of safe and effective vaccines to these pathogens. To address this problem, we have investigated how virus-specific memory CD8+ T cells contribute to protection from a secondary virus infection. Our published studies have demonstrated that the rapid accumulation of circulating memory CD8+ T cells at the site of infection, such as the lung airways, play an important role in limiting early viral replication during a secondary challenge. However, the mechanism(s) by which memory CD8+ T cells recruited to the lung airways limit early viral replication are not known. Therefore, in the current application we will investigate the mechanism(s) that memory CD8+ T cells in the lung airways employ to limit early viral replication during a respiratory infection. First, we will investigate the regulation of cytolytic protein expression in memory CD8+ T cells, and how this expression is influenced by inflammatory cytokines. Second, we will extend these studies to determine how these molecules impact the cytolytic potential of memory CD8+ T cells and how this relates to protective immunity. Together, these studies will identify the mechanism(s) that govern the protective immunity mediated by memory CD8+ T cell in the lung airways and will be important for the rational design of cell- mediated vaccines to respiratory pathogens.

描述（由申请人提供）： 项目描述：呼吸道的粘膜表面与周围环境直接接触，因此是人类病原体（如流感和parainfluenza病毒）的主要入口。这些病毒构成的重大公共卫生威胁强调了开发更有效的疫苗，旨在促进强大而持久的肺免疫。但是，我们对细胞免疫如何促进呼吸道病毒的影响的不完全理解使对这些病原体的安全有效疫苗的发展变得复杂。为了解决这个问题，我们研究了病毒特异性记忆CD8+ T细胞如何促进免受继发性病毒感染的影响。我们发表的研究表明，循环记忆CD8+ T细胞在感染部位的迅速积累，例如肺气道，在限制次要挑战期间限制早期病毒复制方面起着重要作用。然而，尚不清楚为肺气道募集到肺气道的记忆CD8+ T细胞限制早期病毒复制的机制。因此，在当前的应用中，我们将研究肺气道中记忆CD8+ T细胞在呼吸道感染过程中限制早期病毒复制的机制。首先，我们将研究记忆CD8+ T细胞中细胞溶解蛋白表达的调节，以及该表达如何受炎性细胞因子的影响。其次，我们将扩展这些研究，以确定这些分子如何影响记忆CD8+ T细胞的细胞溶性以及与保护性免疫的关系。总之，这些研究将确定控制肺气道中记忆CD8+ T细胞介导的保护性免疫的机制，对于对呼吸道病原体的细胞介导的疫苗的合理设计非常重要。