Spontaneous development of an autoimmune hepatitis - primary biliary cholangitis overlap syndrome in dnTGFβRII Aire -/- mice.

Autoimmune regulator (Aire) and TGF-β signaling play important roles in central tolerance and peripheral tolerance respectively, by eliminating or suppressing the activity of autoreactive T cells. We have previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC) -like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that while dnTGFβRII Aire -/- mice do manifest key histologic and serologic features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA-seq and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFβRII Aire -/- mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8 + T cell infiltrates. Depleting CD8 + T cells using an anti-CD8α antibody significantly alleviated hepatic inflammation and prolonged the lifespan of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8 + T cells. In conclusion, these mice develop an autoreactive CD8 + T-cell mediated autoimmune cholangitis with concurrent hepatitis that exhibits key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. This article is protected by copyright. All rights reserved.