Background:
The pathogenesis of autoimmune hepatitis (AIH) and the mechanisms responsible for the loss of tolerance to hepatic antigens are not clear.
Methods:
We generated a mouse model of AIH that is characterized by conditional hepatocellular expression of an MHC class II-restricted CD4 T cell epitope of lymphocytic choriomeningitis virus (GP61 – 80), and by abundance of cognate CD4 T cells recognizing GP61 – 80.
Results:
The mouse model is characterized by spontaneous development of CD4 T cell-driven hepatitis with typical hallmarks of human AIH, including elevated serum ALT, AST and IgG levels, lymphocytic periportal infiltrates with interface hepatitis, and antinuclear autoantibodies. GP61 – 80-specific T cells were abundantly present in the periphery, notably in the liver, due to the lack of thymic negative selection. As reported for human AIH (Bovensiepen and Schakat et al; J Immunol; in press), autoreactive CD4 effector T cells were characterized by IFNg and TNF co-production. Activation and pathogenic maturation of GP61 – 80-specific T cells seemed to occur locally in the liver within transiently formed portal ectopic lymphoid structures. Moreover, we observed a selective increase of plasticity and instability in GP61 – 80-specific regulatory T cells (Tregs) in the liver, but not of non-specific Tregs. Selective Treg instability was marked by IL-17 production, reduced Foxp3 expression and reduced demethylation of the Foxp3 gene locus.
Conclusions:
Our findings indicate that AIH is driven locally in the liver by a selective failure of autoreactive Tregs to control the pathogenic maturation of autoreactive CD4 effector T cells producing IFNg and TNF.
