Document text
Principal Investigator: Eva Billerbeck
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $420,000
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Acute><Address><Adoptive Cell Transfers><Animal Model><Animal Models and Related Studies><Antigenic Determinants><B cell growth factor><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor-1><BCDF-1><BCGF><BCGF-1><BCSF 1><BSF-1><BSF1><Binding Determinants><Binetrakin><Biological><Biology><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Chronic><Chronic Hepatitis C><Chronic type C viral hepatitis><Chronic viral hepatitis C><Cirrhosis><Class I Genes><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Development><Disease Progression><Epitopes><Equilibrium><Fibrosis><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Generations><HBV><HCV><HCV Vaccination><HCV Vaccine><HCV infection><Hepacivirus><Hepatic><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatitis B Virus><Hepatitis C><Hepatitis C Immunization><Hepatitis C Vaccination><Hepatitis C Vaccine><Hepatitis C virus><Hepatitis C virus infection><Hepatitis C-Like Viruses><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatocyte><Hepatoma><Homologous Serum Hepatitis Virus><Human><IL-13><IL-4><IL13><IL4 Protein><Immune><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Immunomodulation><Immunotherapeutic agent><Infection><Inflammation><Inflammatory><Injury to Liver><Interleukin-13><Interleukin-4><Interleukin-4 Precursor><KO mice><Kinetics><Knock-out Mice><Knockout Mice><LYT3><Link><Liver><Liver Cells><Liver Cells Carcinoma><Liver Fibrosis><Liver diseases><Lymphocyte Stimulatory Factor 1><Lymphocyte Subpopulations><Lymphocyte Subset><MCGF-2><MHC Class I><MHC Class I Genes><Mast Cell Growth Factor-2><Mediating><Mediator><Memory><Metabolic stress><Mice><Mice Mammals><Modeling><Modern Man><Mouse Strains><Murine><Mus><Norway Rats><Null Mouse><Pathology><Patients><Phenotype><Play><Predisposition><Primary carcinoma of the liver cells><Property><Rattus norvegicus><Rodent><Rodentia><Rodents Mammals><Role><Sampling><Steatohepatitis><Susceptibility><T cell response><T-Cell Activation><T-Cell Growth Factor 2><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Time><Tissues><Toxin><Translating><Viral><Viral Diseases><Viral hepatitis><Virus><Virus Diseases><activate T cells><acute infection><adoptive cell therapy><adoptive cellular therapy><balance><balance function><biologic><chronic HCV infection><chronic hepatitis C virus infection><chronic infection><chronic liver inflammation><cirrhotic><compare to control><comparison control><cytokine><developmental><end stage liver disease><end stage liver failure><experiment><experimental research><experimental study><experiments><fibrotic liver><flow cytophotometry><global gene expression><global transcription profile><hep C><hepatic body system><hepatic damage><hepatic disease><hepatic fibrosis><hepatic injury><hepatic organ system><hepatitis C virus vaccination><hepatitis C virus vaccine><hepatitis non A non B><hepatitis virus infection><hepatopathy><high dimensionality><host response><immune competent><immune drugs><immune modulation><immune regulation><immune system response><immune-based therapeutics><immunization strategy><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapeutics><immunotherapy agent><in vivo><infection by hepatitis c virus><innovate><innovation><innovative><insight><killer T cell><liver carcinoma><liver damage><liver disorder><liver injury><model of animal><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non A, non B hepatitis><non-A, non-B hepatitis><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><persistent infection><polarized cell><repair><repaired><response><restraint><scRNA-seq><secondary infection><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><thymus derived lymphocyte><tissue repair><transcriptome><vaccination strategy><vaccine strategy><viral infection><virus infection><virus-induced disease>