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Intravascular Immune Surveillance by Anti-viral T Cells

抗病毒 T 细胞的血管内免疫监视

基本信息

批准号：
10304141
负责人：
ULRICH H VON ANDRIAN
金额：
$ 63.66万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-17 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10304141
关键词：
Acute Address Adhesions Affect Antigens Antiviral Response Behavior Biological Blood Blood Vessels Blood capillaries Blood flow CD8-Positive T-Lymphocytes CD8B1 gene Cell Adhesion Molecules Cell Communication Cells Data Diagnostic Effector Cell Endothelial Cells Endothelium Environment Eragrostis Frequencies Gene Expression Profiling Generations Goals Image Immunologic Surveillance Immunologics Infection Inflammation Kinetics Light Long-Term Effects Longevity Lymphocyte Homing Receptors Lymphoid Tissue Malignant Neoplasms Mediating Memory Molecular Names Nature Peripheral Phase Phenotype Physiological Population Process Proliferating Property Proteins Research Role Series Shapes Signal Transduction Spleen Stream Surface Surveys T-Lymphocyte T-Lymphocyte Subsets TRAF6 gene Technology Testing Textbooks Tissues Transgenic Organisms Viral Viral Antigens Virus Virus Diseases Work adaptive immune response arteriole base capillary bed chemokine receptor density differential expression experience experimental study in vivo intravital microscopy microbial multi-photon pathogen recruit response tool transcriptome sequencing venule

项目摘要

CD8 T cells mediate adaptive immune responses against malignant tumors and intracellular pathogens. In order to exert their protective effector functions, they must engage in physical contacts with their targets. Thus, T cells migrate actively within the body in search of cognate antigens. Following encounter of viral antigens, anti-viral T cells make a series of fate decisions that determine their differentiation into phenotypically diverse effector (Teff) and memory cell (Tmem) subsets that possess specialized properties. The rules that govern the magnitude, functional differentiation, migratory properties and life-span of virus-specific T cell subsets are incompletely understood. Recent work has shown that the chemokine receptor CX3CR1 identifies three distinct CD8+ Teff and Tmem subsets that are induced by systemic viral infections. The largest subset expresses high levels of CX3CR1 and is permanently devoid of lymph node homing receptors. Consequently, CX3CR1hi Teff and Tmem (referred to as effector memory cells, or Tem) are abundant in blood and spleen, but absent from other lymphoid tissues. Contrary to the prevailing paradigm, preliminary experiments indicate that CX3CR1hi Teff and Tem are also excluded from the extravascular compartment in non-lymphoid tissues. Instead, multi-photon intravital microscopy observations indicate that large numbers of CX3CR1hi T cells marginate and arrest within venules and then crawl against the blood stream across the capillary bed into arterioles where the CX3CR1hi T cells are found at high density. The present project will explore the hypothesis that crawling Teff and Tem employ unique molecular mechanisms to adhere and migrate within the microvasculature to survey microvascular endothelial cells for antigens and to receive signals that shape the Tmem repertoire. This hypothesis will be addressed in two specific aims: (1.) to characterize the migratory properties of intravascular anti-viral Teff and Tmem; and (2.) to assess the impact of intravascular T cell crawling on Teff and Tmem differentiation and function.

CD8T细胞介导针对恶性肿瘤和细胞内的获得性免疫反应病原体。为了发挥它们的保护效应器功能，它们必须从事身体活动与他们的目标有联系。因此，T细胞在体内活跃地迁移以寻找同源物抗原。在遇到病毒抗原后，抗病毒T细胞会做出一系列的命运决定决定了它们分化为表型不同效应器(Tef)和记忆细胞 (TMEM)具有特殊属性的子集。支配大小的规则，病毒特异性T细胞亚群的功能分化、迁移特性和寿命是不完全理解。最近的研究表明，趋化因子受体CX3CR1 识别三个不同的CD8+TJeff和TMEM亚群，它们是由系统性病毒感染诱导的。最大的亚群表达高水平的CX3CR1，并且永久无淋巴转移寻的受体。因此，CX3CR1hi Tef和TMEM(称为效应器存储单元，或Tem)在血液和脾中含量丰富，但在其他淋巴组织中缺乏。与…相反流行的范式，初步实验表明，CX3CR1hi Tef和Tem也是在非淋巴组织中被排除在血管外腔之外。相反，多光子活体显微镜观察显示，大量CX3CR1hi T细胞边际停在小静脉内，然后顺着血流穿过毛细血管床爬行进入小动脉内可见高密度的CX3CR1hi T细胞。本项目将探索爬行的特夫和特姆使用独特的分子机制来黏附和在微血管系统内迁移以检测微血管内皮细胞的抗原并接收塑造TMEM曲目的信号。这一假设将从两个具体的方面来阐述目标：(1)研究血管内抗病毒药物TJeff和TMEM的迁移特性； (2)探讨血管内T细胞爬行对T细胞分化和TMEM分化的影响功能。