Regulation of memory CD8+ T cell recruitment to the lung

描述（由申请人提供）：肺是许多破坏性人类病原体的主要入口，包括呼吸道病毒，如SARS冠状病毒和禽流感病毒。因此，开发特异性诱导呼吸道持久保护性免疫的疫苗至关重要。然而，开发肺部疫苗的一个重大障碍是我们对肺细胞介导免疫的了解不足。为了填补这一空白，我们在小鼠模型中对呼吸道病毒感染的回忆反应进行了详细的分析。我们的数据表明，不同的记忆性CD8+ T细胞亚群参与了肺部回忆反应的早期和晚期阶段。回忆反应的早期阶段是由非增殖性记忆性CD8+ T细胞介导的，这些细胞在感染的最初几天内通过炎症信号迅速募集到肺气道。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，与被激活的效应T细胞相比，人们对促使循环、非分裂记忆T细胞进入组织或炎症部位的募集机制几乎一无所知。因此，在当前的应用中，我们将确定如何调节T细胞介导的回忆反应的早期阶段。首先，我们将通过分析趋化因子和趋化因子受体的具体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，我们将以这些信息为基础，确定炎症刺激是否可以用来增强全身或粘膜疫苗接种引起的保护性免疫。总之，这些研究将确定调节呼吸道细胞免疫反应的机制，并将对开发促进对呼吸道病原体有效免疫的疫苗具有重要意义。

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.