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

We recently reported that mice with a T cell-restricted expression of a dominant negative form of transforming growth factor P receptor type II (dnTGF Rho beta RII) 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 dnTGF beta RII disruption of the liver and/or alternatively the appearance of autoreactive T cells. First, using dnTGF beta RIIRag1(-/-) 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 dnTGF beta RII mice into B6/Rag(-/-) (Ly 5.2) recipients. In unmanipulated dnTGF beta RII mice, there was a marked increase in CD4(+) and CD8(+) T cell biliary infiltrates with AMA. indeed, B6/Rag(-/-) recipients of dnTGF beta RII 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 dnTGF beta RII mice predominantly developed inflammatory bowel disease associated with higher levels of serum interferon gamma and tumor necrosis factor alpha. Conclusion: These data suggest that in this model of PBC, autoreactive CD8(+) cells destroy bile ducts.