Role of HCV* Hepatocyte in Regulation of Antiviral T cell Immunity

HCV* 肝细胞在抗病毒 T 细胞免疫调节中的作用

• 批准号: 7919878
• 负责人: Young S. Hahn
• 金额: $ 23.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7919878
• 关键词: Acute; Antiviral Agents; Apoptosis; Be++ element; Beryllium; CD4 Positive T Lymphocytes; CD8B1 gene; CTLA4 gene; Cell physiology; Cells; Chronic; Coculture Techniques; Development; Discontinuous Capillary; Epigenetic Process; Functional disorder; Genes; Genome; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; Immune; Immunity; Impairment; Infection; Interferon Type II; Interleukin-17; Interleukin-2; Ligands; Liver; Liver Cirrhosis; Mediating; Outcome; Patients; Play; Population; Primary carcinoma of the liver cells; Production; Proteins; Regulation; Research; Role; Shapes; Site; Staging; T cell differentiation; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Viral; adaptive immunity; base; cytokine; design; insight; interleukin-22; transcription factor

The project 2 of HCV Cooperative Research Center alms to understand the regulation of adaptive Immunity via the Interaction of HCV-infected hepatocytes with CD4 T cells during acute HCV Infection. HCV Infection In humans is remarkably efficient In establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma. CDS T cells are Involved in controlling HCV Infection; but. In chronic HCV patients, severe CD4 and CDS T cell dysfunction has been observed. This suggests that HCV may employ some mechanism to counteract or possibly suppress the host T cell response. The primary site of viral replication is within hepatocytes in the liver. During HCV Infection, there is the increased population of CD4 T cells in the liver sinusoid, which allows close contact with HCV-infected hepatocytes. To determine whether the Interaction of HCV-infected hepatocytyes with CD4 T cells alters CD4 T cell helper function on shaping CDS T cell effector antiviral activity, we conducted co-culture studies of HCV-infected hepatocytes with CD4 T cells. Our preliminary studies, we demonstrated that hepatocytes expressing whole HCV proteins (I.e. HCV+ hepatocytes) upregulated the ligand of PD-1 negative costimulatory molecule, B7-H1, and TGF-b synthesis. In addition, HCV+ hepatocytes are capable of impairing CD4 T cell function including Inhibition of IFN-g production. Based on these findings, we hypothesize that HCV+ hepatocyte-mediated Inhibition of CD4 T cell function plays a pivotal role In Impairing antiviral CDS T cell effector function. To test this hypothesis, we propose three specific alms, we will first explore the mechanism for HCV+ hepatocytemediated Inhibition of CD4 T cell responses. Second, we will determine the impact of HCV+ hepatocyteinduced CD4 T cell dysfunction on regulating antiviral CDS T cell effector function. Lastly, we will examine the status of CD4 T cell differentiation and correlate it with the outcome of HCV infection during acute HCV patients. Results of these studies will provide valuable insight Into designing therapeutic strategies against to HCV Infection.

HCV合作研究中心项目2致力于了解适应性免疫的调节 通过急性 HCV 感染期间 HCV 感染的肝细胞与 CD4 T 细胞的相互作用。丙型肝炎病毒感染 在人类中，在建立病毒持久性方面非常有效，从而导致肝脏发育 肝硬化和肝细胞癌。 CDS T 细胞参与控制 HCV 感染；但。在慢性 HCV患者中，已观察到严重的CD4和CDS T细胞功能障碍。这表明丙型肝炎病毒可能 采用某种机制来抵消或可能抑制宿主 T 细胞反应。主要站点 病毒复制是在肝脏的肝细胞内进行的。 HCV 感染期间，人口数量增加 肝窦中的 CD4 T 细胞，可以与 HCV 感染的肝细胞密切接触。确定 HCV 感染的肝细胞与 CD4 T 细胞的相互作用是否会改变 CD4 T 细胞辅助功能 为了塑造 CDS T 细胞效应抗病毒活性，我们对 HCV 感染的肝细胞进行了共培养研究 与 CD4 T 细胞。我们的初步研究表明，表达完整 HCV 的肝细胞 蛋白质（即 HCV+ 肝细胞）上调 PD-1 阴性共刺激分子 B7-H1 的配体， 和TGF-b的合成。此外，HCV+肝细胞能够损害CD4 T细胞功能，包括 抑制 IFN-g 的产生。基于这些发现，我们假设 HCV+ 肝细胞介导 CD4 T 细胞功能的抑制在损害抗病毒 CDS T 细胞效应功能中起着关键作用。测试 针对这个假设，我们提出了三个具体的方案，我们首先探讨HCV+肝细胞介导的机制 抑制 CD4 T 细胞反应。其次，我们将确定 HCV+ 肝细胞诱导的影响 CD4 T 细胞功能障碍调节抗病毒 CDS T 细胞效应功能。最后，我们将检查 CD4 T 细胞分化的状态及其与急性 HCV 期间 HCV 感染结果的相关性 患者。这些研究的结果将为设计治疗策略提供有价值的见解 丙型肝炎病毒感染。