title: Mouse liver-specific CD8(+) T-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes.
abstract: CD8(+) T-cell immune response to liver antigens is often functionally diminished or absent. This may occur via deletion of these autoaggressive T-cells, through the acquisition of an anergic phenotype, or via active suppression mediated by other cell populations. We generated a double transgenic model in which mice express CD8(+) T-cells specific for the lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) and LCMV-NP as a hepatic neo-autoantigen, to study the immunological response of potentially liver antigen autoaggressive CD8(+) T-cells. Autoreactive transgenic CD8(+) T-cells were analyzed for functionality and cytotoxic effector status. Despite severe peripheral deletion of liver-specific CD8(+) T-cells, a fraction of autoreactive NP-specific CD8(+) T-cells accumulate in liver, resulting in hepatocyte injury and production of auto-antibodies in both male and female mice. NP-specific intrahepatic T-cells showed capacity to proliferate, produce cytokines and up-regulate activation markers. These data provide in vivo evidence that autoreactive CD8(+) T-cells are activated in the liver and developed an inflammatory process, but require additional factors to cause severe autoimmune destruction of hepatocytes. Our new model will provide a valuable tool for further exploration of the immunological response involved in inflammatory liver diseases, including autoimmune hepatitis.
authors.affiliation: Gastroenterology, Hepatology and Nutrition Division, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chabot
authors.forename: Amin
authors.initials: A
authors.lastname: Fakhfakh
authors.forename: Kathie
authors.initials: K
authors.lastname: Béland
authors.forename: Alain
authors.initials: A
authors.lastname: Lamarre
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Fernando
authors.initials: F
authors.lastname: Alvarez
authors.forename: Idriss
authors.initials: I
authors.lastname: Djilali-Saiah
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D019693:Hepatitis, Autoimmune / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D008099:Liver / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009698:Nucleoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D019076:Transgenes / Q000235:genetics
chemical_list: D000956:Antigens, Viral; D009698:Nucleoproteins