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

CD8 T 细胞在流感感染气道中迁移的动态......

基本信息

批准号：
8850801
负责人：
DAVID James TOPHAM
金额：
$ 38.04万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8850801
关键词：
Acute Adhesions Affect Allergic Antiviral Agents Architecture Area Autoimmune Process Basement membrane Binding Blocking Antibodies Blood Vessels CD8B1 gene Cell Line Cell physiology Cells Cleaved cell Collagen Data Defect Dendritic Cells Deposition Disease Effector Cell Elastic Tissue Environment Enzymes Epithelial Epithelial Cells Epithelium Extracellular Matrix Extracellular Matrix Proteins Fibronectins Future Goals Image Imaging Techniques Immigration Immune Immune response Immunity In Vitro Individual Infection Inflammation Inflammatory Response Influenza Integrin Binding Integrins Interferons Knowledge Laminin Lead Ligands Lymphocyte Lymphoid Measures Mediating Membrane Proteins Memory Methods Modeling Modification Molecular Molecular Conformation Mucous Membrane Mus Neutrophil Infiltration Organ Pathogenesis Phase Population Predisposition Production Proteins Publishing Recovery Recruitment Activity Regulation Relative (related person)Resolution Respiratory Mucosa Respiratory System Respiratory tract structure Role Scanning Sentinel Site Structure Structure of parenchyma of lung Structure of respiratory epithelium Surface System T memory cell T-Lymphocyte T-Lymphocyte Subsets Testing Thick Tissues Trachea Translating Trypsin Viral Hemagglutinins Virus Virus Replication base cell motility cytokine cytotoxic density extracellular flu improved influenzavirus innovative technologies integrin alpha1beta1 interstitial killings lamina densa migration neoplastic receptor trafficking

项目摘要

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.

流感病毒感染呼吸道上皮细胞。病毒的有效复制被限制在这个位置，因为需要一种局部表达的类胰酶来将新生的病毒血凝素(HA)表面蛋白切割成其活性构象。细胞毒性CD8+T细胞(CTL)必须运输到粘膜上皮，以介导感染细胞的清除。CTL直接与受感染的上皮细胞接触，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)蛋白组成的厚基底膜(BM)和牢固地附着在BM上的上皮细胞层(病毒的靶标)组成。抗病毒T细胞在物理上与骨髓的ECM成分相互作用，并随着感染和免疫反应的进展对环境的变化做出反应。最终，在病毒被清除后，哨兵驻留的记忆T细胞群被建立起来，以提供未来与病毒相遇的保护。T细胞表达的ECM成分的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发生变化。我们的总体假设是，在流感感染期间和康复后，基底膜发生了活跃的重塑，调节了T细胞在组织中的迁移和组织记忆的形成。我们的目的是：1)明确流感感染时气管细胞外基质蛋白(ECM)重塑与T细胞迁移动力学之间的关系。2)验证整合素依赖和独立的T细胞在流感感染的气管中迁移取决于组织结构和组成的假设。3)验证A1整合素在流感感染后常驻记忆T细胞的分解和形成过程中调节CD8 T细胞在上皮中积聚的预测。到目前为止，用于评估T细胞在组织中的定位和记忆的方法还没有揭示出动态功能。通过将动态和静态成像技术与量化组织结构和组成的变化的能力相结合，开发了用于成像流感特异性T细胞的创新技术，这些变化共同揭示了T细胞与其组织中环境的关键分子相互作用。