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

肝窦内皮细胞(HSEC)控制淋巴细胞向肝脏的募集，发挥重要的免疫调节功能。它们表达非经典的黏附蛋白，结合大分子，并充当T细胞的抗原递呈细胞。在小鼠巨细胞病毒(MCMV)模型中，HSEC负责MCMV在肝脏中的潜伏和重新激活。MCMV感染小鼠HSEC可诱导多种趋化因子和黏附分子的基因表达。此外，在共培养的同种异体T细胞中，它促进了从免疫耐受到有效的效应反应的转换。因此，有证据表明，急性和潜伏的巨细胞病毒感染肝内皮细胞将调节肝脏招募和激活淋巴细胞的能力，从而提供了一种机制来解释巨细胞病毒感染不仅可以引发临床意义上的肝炎，还可以在移植物排斥反应中增加肝脏的免疫激活。然而，目前还没有关于人巨细胞病毒(HCMV)感染对T细胞进入肝脏的影响的数据。获得人类CMV毒株和分离HCMV特异性T细胞的能力将使我们能够首次在人类细胞系统中研究这些过程。在这项工作中，我们将通过转录和蛋白质组学比较感染和未感染的HSEC，以确定可能影响淋巴细胞相互作用的因素。在基于流动的黏附试验中，将比较来自感染和未感染人巨细胞病毒患者的HSEC从流动中招募淋巴细胞的能力，包括HCMV特异性CD8 T细胞。使用抗体和抑制剂来阻断候选的黏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方案。

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.