Intravascular Immune Surveillance by Anti-viral T Cells

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。

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.