Adoptive transfer of CD8+ T cells from transforming growth factor beta receptor type II (dominant negative form) induces autoimmune cholangitis in mice

Abstract

We recently reported that mice with a T cell–restricted expression of a dominant negative form of transforming growth factor β receptor type II (dnTGFβRII) spontaneously develop autoimmune cholangitis that resembles human primary biliary cirrhosis (PBC), including antimitochondrial antibodies (AMAs) and extensive portal CD4⁺ and CD8⁺ lymphocytic infiltrates. On the basis of these data, we performed a series of experiments to determine whether the pathology was secondary to direct dnTGFβRII disruption of the liver and/or alternatively the appearance of autoreactive T cells. First, using dnTGFβRIIRag1^−/− mice, we noted a normal hepatic and biliary structure. Hence, we performed a rigorous series of adoptive transfer studies, transferring Ly5.1⁺ unfractionated spleen cell CD4⁺ or CD8⁺ T cells from dnTGFβRII mice into B6/Rag^−/− (Ly 5.2) recipients. In unmanipulated dnTGFβRII mice, there was a marked increase in CD4⁺ and CD8⁺ T cell biliary infiltrates with AMA. Indeed, B6/Rag^−/− recipients of dnTGFβRII unfractionated cells develop features of liver disease similar to PBC, suggesting that splenic loss of self-tolerance alone is sufficient to cause disease in this model and therefore that there is no specific abnormality in the biliary targets required for appearance of disease. More importantly, adoptive transfer of CD8⁺ but not CD4⁺ T cells into B6/Rag^−/− mice led to liver histopathology remarkably similar to PBC, emphasizing a prominent role for CD8 T cell–mediated pathogenesis. In contrast, B6/Rag^−/− recipients of CD4⁺ T cells from dnTGFβRII mice predominantly developed inflammatory bowel disease associated with higher levels of serum interferon γ and tumor necrosis factor α. Conclusion: These data suggest that in this model of PBC, autoreactive CD8⁺ cells destroy bile ducts. (HEPATOLOGY 2008.)