Mouse liver-specific CD8+ T-cells encounter their cognate antigen and acquire capacity to destroy target hepatocytes

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.

► We generated a new double transgenic model of autoimmune hepatitis.
► Transgenic mice show an incomplete deletion of autoreactive CD8+ T-cells.
► Remaining autoreactive CD8+ T-cells accumulate in the liver.
► Autoreactive CD8+ T-cells acquire an effector phenotype.
► Mice sera show elevated transaminases (ALT) level, auto-antibodies and inflammation.