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

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病毒和副流感病毒的主要入口。这些病毒造成的重大公共卫生威胁突出了开发更有效的疫苗的必要性，这些疫苗旨在促进强大和持久的肺部免疫。然而，我们对细胞免疫如何有助于保护免受呼吸道病毒的不完全理解，使得针对这些病原体的安全有效疫苗的开发变得复杂。为了解决这个问题，我们研究了病毒特异性记忆CD8+ T细胞如何有助于保护免受继发性病毒感染。我们已发表的研究表明，循环记忆CD8+ T细胞在感染部位（如肺气道）的快速积累在二次攻击期间限制早期病毒复制方面发挥重要作用。然而，记忆CD8+ T细胞募集到肺气道限制早期病毒复制的机制尚不清楚。因此，在本申请中，我们将研究肺气道中的记忆CD8+ T细胞用于限制呼吸道感染期间的早期病毒复制的机制。首先，我们将研究记忆性CD8+ T细胞中溶细胞蛋白表达的调节，以及这种表达如何受到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性CD8+ T细胞的细胞溶解潜力，以及这与保护性免疫的关系。总之，这些研究将确定肺气道中记忆CD8+ T细胞介导的保护性免疫的机制，并且对于合理设计针对呼吸道病原体的细胞介导的疫苗将是重要的。

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.