Recruitment of memory CD8+ T cells to the lung airways

描述(申请人提供)：呼吸道病毒是全球发病率和死亡率的主要原因。在初次感染或接种疫苗后建立的记忆CD8+T细胞，通过在肺组织和肺气道中快速积累抗原特异性细胞，提供对二次病毒攻击的保护。阐明影响记忆T细胞向肺部呼吸道募集的因素，对于设计未来用于促进细胞免疫的疫苗具有重要意义。在目前的研究中，我们将利用已建立的呼吸道病毒感染(仙台病毒)模型来研究记忆CD8 T细胞在炎症反应中向肺部呼吸道的募集。有趣的是，尽管许多研究调查了效应性T细胞在肺部的募集，但关于已建立的记忆T细胞的募集的公开数据很少。初步数据显示，不同的Toll样受体(TLR)配体可以诱导记忆T细胞重新聚集到肺气道。然而，在稳定状态和炎症条件下，控制肺内呼吸道募集的机制尚不清楚。该方案的基本假设是，TLR配体诱导一系列趋化因子的表达，这些趋化因子是记忆CD8 T细胞重新聚集到肺部呼吸道所必需的。这一假设将通过(I)表征TLR配体刺激后的趋化因子的表达，并确定这些趋化因子与肺气道募集的相关性，以及(Ii)确定TLR配体通过将记忆CD8 T细胞募集到肺呼吸道来增强免疫小鼠的保护性免疫的能力来检验这一假说。研究与公共卫生的相关性：目前针对流感等呼吸道病毒的疫苗是不够的，因为它们只提供针对特定病毒株的季节性保护。针对病毒内部成分不变的细胞疫苗将对一系列流感病毒株产生广泛的保护作用，从而最大限度地减少重复接种疫苗的需要，并简化疫苗生产。目前的提议将研究记忆T细胞被招募到呼吸道病毒感染部位的机制，这对未来基于细胞的疫苗的设计具有重要意义。

DESCRIPTION (provided by applicant): Respiratory viruses are a major cause of morbidity and mortality worldwide. Memory CD8+ T cells, established after primary infection or vaccination, confer protection against a secondary virus challenge through the rapid accumulation of antigen-specific cells in the lung tissue and lung airways. Elucidation of the factors governing the recruitment memory T cells to the lung airways is of great importance for the design of future vaccines designed to promote cellular immunity. In the present proposal, we will take advantage of the well-established model of respiratory virus infection (Sendai virus) to investigate the recruitment of memory CD8 T cells to the lung airways in response to inflammation. Interestingly, despite numerous studies investigating the recruitment of effector T cells the lungs, there is very little published data regarding the recruitment of established memory T cells. Preliminary data show that different toll-like receptor (TLR) ligands can induce recruitment of memory T cells into the lung airways. However, the mechanisms governing recruitment to the lung airways under steady-state and inflammatory conditions are not known. The underlying hypothesis of the proposal is that TLR ligands induce the expression of a set of chemokines that are required for the recruitment of memory CD8 T cells to the lung airways. This hypothesis will be tested by (i) characterizing the expression of chemokines following TLR ligand stimulation and determining the relevance of these chemokines for recruitment to the lung airways, and (ii) determining the ability of TLR ligands to boost protective immunity in vaccinated mice through the recruitment of memory CD8 T cells to the lung airways. Relevance of research to public health: Current vaccines against respiratory viruses such as influenza are inadequate in that they provide only seasonal protection against specific strains of the virus. A cellular- based vaccine, directed against the unchanging internal components of the virus, would confer broad protection against a range of influenza strains, thereby minimizing the need for repeated vaccinations and simplifying vaccine production. The current proposal will investigate the mechanisms by which memory T cells are recruited to the site of respiratory virus infection, which has important implications for the design of future cellular-based vaccines.