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。为了发挥其保护性效应器功能，它们必须从事身体活动与他们的目标接触。因此，T 细胞在体内积极迁移，寻找同源细胞。抗原。遇到病毒抗原后，抗病毒 T 细胞做出一系列命运决定决定它们分化为表型多样化的效应细胞 (Teff) 和记忆细胞 (Tmem) 具有特殊属性的子集。控制大小的规则，病毒特异性 T 细胞亚群的功能分化、迁移特性和寿命不完全理解。最近的工作表明趋化因子受体CX3CR1 确定了由系统性病毒感染诱导的三个不同的 CD8+ Teff 和 Tmem 子集。最大的子集表达高水平的 CX3CR1，并且永久没有淋巴结归巢受体。因此，CX3CR1hi Teff 和 Tmem（称为效应记忆细胞，或 Tem）在血液和脾脏中含量丰富，但在其他淋巴组织中不存在。与此相反流行的范式，初步实验表明 CX3CR1hi Teff 和 Tem 也是排除在非淋巴组织的血管外室之外。相反，多光子活体显微镜观察表明大量 CX3CR1hi T 细胞边缘化并在小静脉内停留，然后逆着血流爬过毛细血管床进入 CX3CR1hi T 细胞以高密度存在的小动脉。本项目将探索爬行的 Teff 和 Tem 采用独特的分子机制来粘附和粘附的假设在微血管系统内迁移以调查微血管内皮细胞的抗原并接收塑造 Tmem 曲目的信号。这个假设将通过两个具体的目的：(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 细胞爬行对 Teff 和 Tmem 分化的影响功能。