Regulation of memory CD8+ T cell recruitment to the lung

描述(申请人提供)：肺部是许多毁灭性的人类病原体进入的主要门户，包括呼吸道病毒，如SARS冠状病毒和禽流感病毒。因此，开发能够在呼吸道中诱导持久保护性免疫的疫苗至关重要。然而，发展肺部疫苗的一个重要障碍是我们对肺内细胞免疫的了解不足。为了填补这一知识空白，我们对小鼠模型中呼吸道病毒感染的召回反应进行了详细的分析。我们的数据表明，不同的记忆CD8+T细胞亚群在肺内回忆反应的早期和晚期都有贡献。回忆反应的早期阶段是由非增殖性CD8+T细胞介导的，在感染的最初几天，这些细胞被炎症信号迅速招募到肺部呼吸道。这些细胞通过限制病毒复制发挥关键作用，直到激活的效应细胞开始到达。然而，与激活的效应器T细胞相比，几乎没有人知道驱动循环的、非分裂的记忆T细胞招募到组织或炎症部位的机制。因此，在目前的应用中，我们将确定T细胞介导的回忆反应的早期阶段是如何调节的。首先，我们将通过分析趋化因子和趋化因子受体的特定作用来确定在回忆反应中调节记忆T细胞运输的机制。其次，我们将根据这些信息来确定是否可以利用炎症刺激来提高全身或粘膜疫苗接种所引起的保护性免疫。总之，这些研究将确定调节呼吸道细胞免疫反应的机制，并将对促进对呼吸道病原体的有效免疫的疫苗的开发至关重要。

DESCRIPTION (provided by applicant): The lung is a major portal of entry for many devastating human pathogens including respiratory viruses, such as the SARS corona virus and avian influenza viruses. Therefore, it is critical to develop vaccines that specifically induce long-lasting protective immunity in the respiratory tract. However, a significant hurdle in the development of pulmonary vaccines is our poor understanding of cell-mediated immunity in the lung. To fill this gap in our knowledge, we have undertaken a detailed analysis of the recall response to respiratory virus infections in the mouse model. Our data demonstrate that distinct subpopulations of memory CD8+ T cells contribute to the early and late stages of the recall response in the lung. The early phase of the recall response is mediated by non-proliferating memory CD8+ T cells that are rapidly recruited to the lung airways by inflammatory signals during the first few days of infection. These cells play a key role by limiting viral replication until activated effector cells start to arrive. However, in contrast to activated effector T cells, there is almost nothing known about the mechanisms that drive the recruitment of circulating, non- dividing memory T cells into the tissues or into inflammatory sites. Therefore, in the current application we will determine how the early stages of a T cell mediated recall response are regulated. First, we will identify the mechanisms that regulate memory T cell trafficking during a recall response by analyzing the specific roles of chemokines and chemokine receptors. Second, we will build on this information to determine whether inflammatory stimuli can be utilized to boost protective immunity elicited by either systemic or mucosal vaccination. Together, these studies will identify the mechanisms that regulate cellular immune responses in the respiratory tract and will be important for the development of vaccines that promote effective immunity to respiratory pathogens.