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：
10509385
负责人：
ULRICH H VON ANDRIAN
金额：
$ 63.79万
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/10509385
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 Exclusion Frequencies Gene Expression Profiling Generations Germ Cells Goals Image Immunologic Surveillance Immunologics Infection Kinetics 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 T-cell inflamed TRAF6 gene Technology Testing Textbooks Tissues Transgenic Organisms Vascular Endothelial Cell Viral Viral Antigens Virus Virus Diseases Work adaptive immune response arteriole capillary bed cell motility chemokine receptor density differential expression experience experimental study in vivo intravital microscopy microbial migration 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.

CD8 T细胞介导针对恶性肿瘤和细胞内的适应性免疫反应病原体。为了发挥保护性效应器功能，他们必须从事身体与他们的目标接触。因此，T细胞在体内主动迁移以寻找同源抗原。遇到病毒抗原后，抗病毒T细胞做出一系列命运决定这决定了它们分化为表型多样的效应子（TEFF）和记忆细胞（TMEM）具有专门特性的子集。控制大小的规则，病毒特异性T细胞子集的功能分化，迁移特性和寿命为不完全理解。最近的工作表明趋化因子受体CX3CR1 鉴定由全身病毒感染诱导的三个不同的CD8+ TEFF和TMEM子集。最大的子集表示高水平的CX3CR1，并永久没有淋巴结归巢受体。因此，CX3CR1HI TEFF和TMEM（称为效应记忆单元，或TEM）充满血液和脾脏，但没有其他淋巴组织。与盛行的范式，初步实验表明CX3CR1HI TEFF和TEM也是在非淋巴组织的血管外室中排除。而是多光子弹性显微镜观测表明，大量的CX3CR1HI T细胞缘缘并在静脉里停止，然后爬在毛细血管床上的血液中在高密度下发现CX3CR1HI T细胞的小动脉。本项目将探索爬行Teff和Tem采用独特的分子机制来粘附的假设迁移在微血管内部，调查抗原的微血管内皮细胞和接收塑造TMEM曲目的信号。该假设将以两个特定目的：（1.）表征血管内抗病毒TEFF和TMEM的迁移特性；和（2.）评估血管内T细胞爬网对TEFF和TMEM分化以及功能。