title: The level of viral antigen presented by hepatocytes influences CD8 T-cell function.
abstract: CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha). On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-gamma and TNF-alpha production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.
authors.affiliation: UCL Institute of Hepatology, Royal Free and University College Medical School, London, UK.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Gehring
authors.forename: Dianxing
authors.initials: D
authors.lastname: Sun
authors.forename: Patrick T F
authors.initials: PT
authors.lastname: Kennedy
authors.forename: Esther
authors.initials: E
authors.lastname: Nolte-'t Hoen
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
authors.forename: Shanthi
authors.initials: S
authors.lastname: Wasser
authors.forename: Clare
authors.initials: C
authors.lastname: Selden
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
authors.forename: Dan M
authors.initials: DM
authors.lastname: Davis
authors.forename: Michael
authors.initials: M
authors.lastname: Nassal
authors.forename: Antonio
authors.initials: A
authors.lastname: Bertoletti
mesh_terms: D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation
chemical_list: D000956:Antigens, Viral; D007371:Interferon-gamma