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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.

CD 8 T细胞介导针对恶性肿瘤的适应性免疫应答，病原体为了发挥它们的保护效应器功能，它们必须参与物理活动，与他们的目标接触。因此，T细胞在体内积极迁移以寻找同源物。抗原在遇到病毒抗原后，抗病毒T细胞做出一系列命运决定其决定了它们分化成表型多样性效应细胞（Teff）和记忆细胞（THEORY）具有专门属性的子集。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。最近的研究表明趋化因子受体CX 3CR 1 鉴定了由系统性病毒感染诱导的三种不同的CD 8 + Teff和Teff亚群。最大的亚群表达高水平的CX 3CR 1，并且永久性地没有淋巴结转移。归巢受体因此，CX 3CR 1hi Teff和Teff（称为效应记忆细胞，或Tem）在血液和脾脏中丰富，但在其他淋巴组织中缺乏。违反在流行的范例中，初步实验表明CX 3CR 1hi Teff和Tem也是从非淋巴组织的血管外隔室中排除。相反，多光子活体显微镜观察表明，大量CX 3CR 1hi T细胞边缘化，并在小静脉内停滞，然后逆着血流爬行穿过毛细血管床，小动脉中发现高密度的CX 3CR 1hi T细胞。本项目将探讨爬行Teff和Tem采用独特的分子机制粘附和在微血管系统内迁移以检测微血管内皮细胞的抗原，接收信号来塑造Tendon的所有功能。这一假设将在两个具体的目的：（1.）表征血管内抗病毒Teff和Teff的迁移性质;和（2.）评估血管内T细胞爬行对Teff和Teff分化的影响，功能