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Human Cytomegalovirus Infection of Human Hepatic Sinusoidal Endothelial Cells Modulates T Cell Recruitment into the Liver

人类巨细胞病毒感染人肝窦内皮细胞调节 T 细胞招募至肝脏

基本信息

批准号：
193989736
负责人：
Professor Dr. Tony Bruns
金额：
--
依托单位：
Klinik für Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin (Med. Klinik III)
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2010
资助国家：
德国
起止时间：
2009-12-31 至 2012-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/193989736?language=en
关键词：
Human Cytomegalovirus Infection Hepatic Sinusoidal

项目摘要

Hepatic sinusoidal endothelial cells (HSEC) control lymphocyte recruitment into the liver and fulfil important immune regulatory functions. They express non-classical adhesion proteins, bind macromolecules, and act as antigen-presenting cells to T cells. In a model of murine cytomegalovirus (mCMV) HSEC were responsible for mCMV latency and reactivation in the liver. MCMV infection of murine HSEC induces the gene expression of several chemokines and adhesion molecules. Furthermore, it promotes the switch from immunotolerance to a potent effector response in co-cultured allogeneic T cells. Thus, there is evidence to suggest that acute and latent CMV infection of hepatic endothelium will modulate the ability of the liver to recruit and activate lymphocytes thereby providing a mechanism to explain how CMV infection can not only provoke a clinically significant hepatitis but also increase hepatic immune activation in graft rejection.However, no data exist on the influence of human CMV (hCMV) infection on T cell recruitment into the liver. The access to human strains of CMV and the ability to isolate hCMV specific T cells will allow investigating these processes for the first time in human cell systems. In this work, we will compare infected and non-infected HSEC by transcriptomic and proteomic profiling to determine factors that might influence lymphocyte interaction. In a flow-based adhesion assay HSEC from hCMV-infected and non-infected patients will be compared for their ability to recruit lymphocytes from flow, including hCMV-specific CD8+ T cells. The use of antibodies and inhibitors to block candidate adhesion molecules and chemokines will help determining cellular and soluble factors that promote leukocyte recruitment. Furthermore, we will determine whether hCMV-infection modulates the ability of HSEC to activate allogeneic T cells, which is particularly relevant in the context of hCMV infection and graft rejection and may provide innovative therapy options.

肝窦内皮细胞（HSEC）控制淋巴细胞向肝脏的募集，并履行重要的免疫调节功能。它们表达非经典粘附蛋白，结合大分子，并作为T细胞的抗原呈递细胞。在鼠巨细胞病毒（mCMV）模型中，HSEC负责mCMV在肝脏中的潜伏期和再激活。 MCMV感染小鼠HSEC诱导几种趋化因子和粘附分子的基因表达。此外，它促进从免疫耐受性的转换到一个有效的效应反应在共培养的同种异体T细胞。因此，有证据表明肝内皮的急性和潜伏性CMV感染将调节肝脏募集和活化淋巴细胞的能力，从而提供了一种机制来解释CMV感染如何不仅可以引起临床显著的肝炎，而且还可以增加移植物排斥中的肝脏免疫活化。没有关于人CMV（hCMV）感染对T细胞募集到肝脏中的影响的数据。获得CMV的人株和分离hCMV特异性T细胞的能力将允许首次在人细胞系统中研究这些过程。在这项工作中，我们将比较感染和未感染的HSEC的转录组和蛋白质组分析，以确定可能影响淋巴细胞相互作用的因素。在基于流动的粘附测定中，将比较来自hCMV感染和未感染患者的HSEC从流动募集淋巴细胞（包括hCMV特异性CD8+ T细胞）的能力。使用抗体和抑制剂来阻断候选粘附分子和趋化因子将有助于确定促进白细胞募集的细胞和可溶性因子。此外，我们将确定hCMV感染是否调节HSEC激活同种异体T细胞的能力，这在hCMV感染和移植物排斥的背景下特别相关，并可能提供创新的治疗选择。