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：
10500968
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/10500968
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 Lead Light Link Liver Liver Fibrosis Liver diseases Lymphocyte Subset MHC Class I Genes Mediating Mediator of activation protein 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 base cell type chronic infection chronic liver inflammation 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 secondary infection single-cell RNA sequencing tissue repair transcriptome vaccination strategy vaccine strategy

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 Lead Light Link Liver Liver Fibrosis Liver diseases Lymphocyte Subset MHC Class I Genes Mediating Mediator of activation protein 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 base cell type chronic infection chronic liver inflammation 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 secondary infection single-cell RNA sequencing tissue repair transcriptome vaccination strategy vaccine strategy

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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.

炎性肝疾病，例如慢性丙型肝炎病毒（HCV）感染可以发展为肝纤维化和肝细胞癌（HCC）。肝T细胞免疫与肝病紧密相关，因为T细胞不是仅对于清除HCV（例如HCV）的肝病病毒至关重要，但也可能导致肝损伤并造成贡献疾病进展。但是，功能上不同的CD4+和CD8+ T细胞子集的具体作用或介导有效的抗病毒免疫反应或调节炎症期间的肝脏损害尚不清楚。因此，获得了新的见解肝T细胞亚群的功能生物学是发展HCV疫苗策略和治疗进行性肝病的免疫治疗选择。有限获取人肝组织，缺乏免疫能力的小动物模型已阻碍肝抗病毒免疫机制的研究。但是，我们最近开发了一种免疫能力的 HCV相关病毒的小鼠模型，挪威大鼠肝病毒（NRHV），该模型具有重要的病毒学和重要的病毒学和与人类HCV感染的免疫学相似性。此进步现在允许深入机械体内抗肝病免疫的研究。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显示多种抗病毒1 T细胞反应和T细胞依赖性病毒清除率的显着诱导。然而，我们还意外地观察到肝CD8+ T细胞和NKT细胞的子集是极化的对2型免疫力，可能有助于免疫调节。在此提案中，我们将基于这些初步数据并阐明不同肝1 T细胞的功能性能和潜在串扰和2型细胞因子在NRHV感染期间分泌淋巴细胞亚群。具体来说，我们将使用高维流式细胞仪，体内功能方法和/或转录组分析至1）定义不同病毒特异性效应子和记忆CD8+ T细胞子集的功能作用，2）确定动力学和 CD4+ T细胞对病毒特异性CD8+ T细胞的产生和保护性免疫的影响，3）描绘 2型CD8+和NKT细胞子集的功能，并定义其对肝损伤，病毒特异性T细胞和在不同感染阶段，其他肝免疫细胞。最后，我们旨在将我们的主要发现从小鼠模型与人类HCV患者。我们的数据将提供有关不同肝1和2型T细胞的作用和相互作用的新型生物学见解和NKT细胞亚群，以介导病毒清除率，保护性免疫，组织病理或修复体内肝病感染。