title: Effective intrahepatic CD8+ T-cell immune responses are induced by low but not high numbers of antigen-expressing hepatocytes.
abstract: Liver infections with hepatotropic viruses, such as hepatitis B virus and hepatitis C virus are accompanied by viral persistence and immune failure. CD8+ T cells are crucial mediators of the intrahepatic antiviral immune response. Chronic infections of the liver and other organs correlate with T-cell exhaustion. It was previously suggested that high antigen load could result in T-cell exhaustion. We aimed at elucidating the impact of different intrahepatic antigen loads on the quality of CD8+ T-cell-mediated immunity by employing an infection-free transgenic mouse model expressing ovalbumin (Ova) as the target antigen. Adoptive transfer of OT-I cells induced a transient intrahepatic immune response toward both high and low Ova levels. However, antigen clearance was achieved only in mice expressing low antigen levels. In contrast, T cells exposed to high antigen levels underwent exhaustion and became depleted, causing antigen persistence. Moreover, when functional T cells were exposed to high intrahepatic antigen levels, a complete transition toward exhaustion was observed. Thus, this study shows that the antigen expression level in the liver correlates inversely with T-cell immunity in vivo and governs the efficiency of immune responses upon antigen presentation.
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
authors.forename: Aaron
authors.initials: A
authors.lastname: Ochel
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
authors.forename: Marcin
authors.initials: M
authors.lastname: Cebula
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Riehn
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
authors.forename: Upneet
authors.initials: U
authors.lastname: Hillebrand
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lipps
authors.affiliation: Clinic for Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Hauser
authors.affiliation: Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany.|Experimental Hematology, Medical School Hannover, Carl-Neuberg-Str. 10, D-30625 Hannover, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wirth
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006505:Hepatitis / Q000276:immunology / Q000473:pathology; D022781:Hepatocytes / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008810:Mice, Inbred C57BL
chemical_list: D000941:Antigens