Dynamics of CD8 T cell migration in the influenza-infected airways ....

流感病毒感染呼吸道的上皮细胞。由于需要局部表达的胰蛋白酶样酶将新生病毒血凝素（HA）表面蛋白切割成其活性构象，因此病毒的生产性复制仅限于该位点。细胞毒性CD8+ T细胞（CTL）必须运输到粘膜上皮以介导感染细胞的消除。CTL直接与受感染的上皮细胞结合，但允许它们进入组织、迁移和定位受感染细胞的机制仍不清楚。呼吸道上皮由细胞外基质（ECM）蛋白质制成的厚基底膜（BM）和牢固附着于BM的上皮细胞层（病毒的靶点）组成。抗病毒T细胞与BM的ECM组分物理相互作用，并随着感染和免疫应答的进展对该环境的变化做出反应。最终，在病毒被清除后，建立了一个哨兵驻留记忆T细胞群，以提供保护，防止未来遇到病毒。由T细胞表达的ECM组分特异性受体已被证明对这些组织记忆T细胞的建立至关重要，尽管其功能似乎随着感染从急性期进展到恢复期而转变。我们的总体假设是，在流感感染期间和恢复后，基底膜发生主动重塑，调节组织中T细胞的迁移和组织记忆的形成。我们的目标是：1）确定流感感染期间气管中细胞外基质蛋白（ECM）的重塑与T细胞迁移动力学之间的关系。2)检验流感感染气管中整合素依赖性和非依赖性T细胞迁移取决于组织结构和组成的假设。3)检验α 1整联蛋白在流感感染后驻留记忆T细胞的消退和形成过程中调节上皮中CD8 T细胞积聚的预测。到目前为止，用于评估组织中T细胞定位和记忆的方法尚未揭示动态功能。已经开发了创新技术，通过将动态和静态成像技术与定量组织结构和组成变化的能力相结合，对流感特异性T细胞进行成像，这些变化共同揭示了T细胞与组织中环境的关键分子相互作用。

Influenza virus infects the epithelial cells that line the respiratory tract. Productive replication of the virus is restricted to this site because of the requirement for a locally expressed trypsin-like enzyme to cleave nascent viral hemagglutinin (HA) surface protein into its active conformation. Cytotoxic CD8+ T cells (CTL) must traffic to the mucosal epithelium to mediate elimination of infected cells. The CTL directly engage infected epithelial cells, yet the mechanisms that allow them to enter the tissue, migrate and locate infected cells remain poorly defined. The respiratory epithelium is comprised of a thick basement membrane (BM) made of extracellular matrix (ECM) proteins, and an epithelial cell layer (the targets of the virus) firmly attached to the BM. The antiviral T cells physically interact with the ECM components of the BM, and react to changes in that environment as the infection and immune response progresses. Ultimately, after the virus is cleared, a population of sentinel resident memory T cells is established to provide protection from future encounters with the virus. Receptors specific for ECM components, expressed by the T cells, have been shown to be critical to the establishment of these tissue memory T cells, though its function appears to shift as the infection progresses from acute to recovery phases. Our overall hypothesis is that active remodeling of the basement membrane occurs during influenza infection and after recovery that regulate the migration of T cells in the tissue and the formation of tissue memory. Our aims are to: 1) Define the relationship between remodeling of extracellular matrix proteins (ECM) in the trachea during influenza infection and dynamics of T cell migration. 2) Test the hypothesis that integrin dependent and independent T cell migration in the influenza-infected trachea depends on tissue architecture and composition. 3) Test the prediction that al integrin regulates CD8 T cell accumulation in the epithelium during resolution and formation of resident memory T cells after influenza infection. Until now, the methods used to assess T cell localization and memory in the tissues have not revealed dynamic functions. Innovative technology has been developed to image influenza-specific T cells by combining dynamic and static imaging techniques with the ability to quantitate changes to the tissue architecture and composition that together reveal critical molecular interactions of T cells with their environment in the tissue.