New insights into the functional diversity of the hepatic antiviral T cell response during hepacivirus infection in vivo

体内肝炎病毒感染期间肝脏抗病毒T细胞反应功能多样性的新见解

基本信息

批准号：
10631150
负责人：
Eva Billerbeck
金额：
$ 42万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631150
关键词：
Acute Address Adoptive Cell Transfers Animal Model Biological Biology CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cells Chronic Chronic Hepatitis C Cirrhosis Cytotoxic T-Lymphocytes Data Development Disease Progression Epitopes Equilibrium Fibrosis Flow Cytometry Generations Hepatic Hepatitis B Virus Hepatitis C Hepatitis C Vaccination Hepatitis C Vaccine Hepatitis C virus Hepatitis C-Like Viruses Hepatocyte Human Immune Immune response Immunity Immunocompetent Immunologics Immunology Immunotherapeutic agent Infection Inflammation Inflammatory Interleukin-13 Interleukin-4 Kinetics Knockout Mice Link Liver Liver Fibrosis Liver diseases Lymphocyte Subset MHC Class I Genes Mediating Mediator Memory Metabolic stress Modeling Mouse Strains Mus Pathology Patients Phenotype Play Predisposition Primary carcinoma of the liver cells Property Rattus norvegicus Rodent Role Sampling Steatohepatitis T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Time Tissues Toxin Translating Viral Viral hepatitis Virus Virus Diseases acute infection chronic infection chronic liver inflammation comparison control cytokine end stage liver disease experimental study high dimensionality immunoregulation in vivo innovation insight liver injury mouse model novel novel therapeutics polarized cell repaired response restraint secondary infection single-cell RNA sequencing tissue repair transcriptome vaccination strategy vaccine strategy

项目摘要

Inflammatory liver diseases such as chronic hepatitis C virus (HCV) infection can progress to liver fibrosis and hepatocellular carcinoma (HCC). Hepatic T cell immunity is closely linked to liver diseases since T cells are not only essential for the clearance of hepatotropic viruses like HCV but may also cause liver injury and contribute to disease progression. However, the specific role of functionally distinct CD4+ and CD8+ T cell subsets or innate-like T cells, such as natural killer T (NKT) cells, in mediating an effective antiviral immune response or regulating liver damage during inflammation are not well understood. Thus, gaining new insights into the functional biology of hepatic T cell subsets is a prerequisite for the development of HCV vaccine strategies and immunotherapeutic options for the treatment of progressive liver diseases. Limited access to human liver tissue and the lack of immune-competent small animal models has impeded studies of hepatic antiviral immune mechanisms. However, we have recently developed an immune-competent mouse model of an HCV-related virus, Norway rat hepacivirus (NrHV), which shares significant virological and immunological similarities with HCV infection in humans. This advance now allows for in-depth mechanistic studies of anti-hepaciviral immunity in vivo. Our initial analysis of hepatic lymphocyte subsets during acute, chronic and secondary NrHV infection revealed a significant induction of a diverse antiviral type 1 T cell response and T cell dependent viral clearance. However, we also made the unexpected observation that subsets of hepatic CD8+ T cells and NKT cells are polarized towards type 2 immunity and may contribute to immune-regulation. In this proposal, we will build on these preliminary data and elucidate the functional properties and potential crosstalk of distinct hepatic type 1 T cells and type 2 cytokine secreting lymphocyte subsets during NrHV infection. Specifically, we will use high- dimensional flow cytometry, in vivo functional approaches and/or transcriptome analysis to 1) define the functional role of different virus-specific effector and memory CD8+ T cell subsets, 2) determine the kinetic and impact of CD4+ T cells on the generation of virus-specific CD8+ T cells and protective immunity, 3) delineate the function of type 2 CD8+ and NKT cell subsets and define their impact on liver damage, virus-specific T cells and other hepatic immune cells during different stages of infection. Finally, we aim to translate our main findings from the mouse model to human HCV patients. Our data will provide novel biological insight into the role and interplay of distinct hepatic type 1 and type 2 T cell and NKT cell subsets in mediating viral clearance, protective immunity, tissue pathology or repair during a hepatotropic virus infection in vivo.

慢性丙型肝炎病毒（HCV）感染等炎症性肝病可进展为肝纤维化，肝细胞癌（HCC）。肝 T 细胞免疫与肝脏疾病密切相关，因为 T 细胞不仅对于清除 HCV 等嗜肝病毒至关重要，但也可能导致肝损伤并促进到疾病进展。然而，功能不同的 CD4+ 和 CD8+ T 细胞亚群的具体作用或先天性 T 细胞，例如自然杀伤 T (NKT) 细胞，介导有效的抗病毒免疫反应或在炎症过程中调节肝损伤尚不清楚。从而获得新的认识肝 T 细胞亚群的功能生物学是开发 HCV 疫苗策略的先决条件用于治疗进行性肝病的免疫治疗选择。人类肝脏组织的获取有限以及缺乏具有免疫能力的小动物模型阻碍了肝脏抗病毒免疫机制研究。然而，我们最近开发了一种具有免疫功能的 HCV 相关病毒挪威大鼠肝炎病毒 (NrHV) 的小鼠模型，其具有显着的病毒学特征和与人类 HCV 感染的免疫学相似性。这一进步现在允许深入的机械体内抗肝炎病毒免疫研究。我们对急性、慢性和继发性 NrHV 感染期间肝淋巴细胞亚群的初步分析表明显着诱导多种抗病毒 1 型 T 细胞反应和 T 细胞依赖性病毒清除。然而，我们还意外地观察到肝脏 CD8+ T 细胞和 NKT 细胞的亚群是极化的 2 型免疫并可能有助于免疫调节。在本提案中，我们将在此基础上初步数据并阐明不同肝 1 型 T 细胞的功能特性和潜在串扰 NrHV 感染期间分泌淋巴细胞亚群的 2 型细胞因子。具体来说，我们将使用高三维流式细胞术、体内功能方法和/或转录组分析 1) 定义不同病毒特异性效应子和记忆 CD8+ T 细胞亚群的功能作用，2) 确定动力学和 CD4+ T 细胞对病毒特异性 CD8+ T 细胞的生成和保护性免疫的影响，3) 描绘 2 型 CD8+ 和 NKT 细胞亚群的功能，并确定它们对肝损伤、病毒特异性 T 细胞和其他肝脏免疫细胞在感染的不同阶段。最后，我们的目标是将我们的主要发现转化为人类 HCV 患者的小鼠模型。我们的数据将为不同肝脏 1 型和 2 型 T 细胞的作用和相互作用提供新的生物学见解 NKT 细胞亚群在介导病毒清除、保护性免疫、组织病理学或修复过程中的作用体内嗜肝病毒感染。