Clonality, activated antigen-specific CD8(+) T cells, and development of autoimmune cholangitis in dnTGFβRII mice.

UNLABELLED: There are several murine models described with features similar to human primary biliary cirrhosis (PBC). Among these models, the one which has the closest serologic features to PBC is a mouse with a T-cell-restricted expression of the dominant negative transforming growth factor β receptor type II (dnTGFβRII). Our work has demonstrated that CD8(+) T cells from dnTGFβRII mice transfer autoimmune cholangitis to Rag1(-/-) recipients. However, it remained unclear whether the autoimmune cholangitis was secondary to an intrinsic function within CD8(+) T cells or due to the abnormal TGFβR environment within which CD8(+) T cells were generated. To address this mechanistic issue, we used our dnTGFβRII, OT-I/Rag1(-/-) , OT-II/Rag1(-/-) mice and in addition generated OT-I/dnTGFβRII/Rag1(-/-) , and OT-II/dnTGFβRII/Rag1(-/-) mice in which the entire T-cell repertoire was replaced with ovalbumin (OVA)-specific CD8(+) or CD4(+) T cells, respectively. Importantly, neither the parental OT-I/dnTGFβRII/Rag1(-/-) mice and/or OT-II/dnTGFβRII/Rag1(-/-) mice developed cholangitis. However, adoptive transfer demonstrated that only transfer of CD8(+) T cells from dnTGFβRII mice but not CD8(+) T cells from OT-I/Rag1(-/-) mice or from OT-I/dnTGFβRII/Rag1(-/-) mice transferred disease. These data were not secondary to an absence of CD4(+) T cell help since a combination of CD8(+) T cells from OT-I/dnTGFβRII/Rag1(-/-) and CD4(+) T cells from OT II/dnTGFβRII/Rag1(-/-) or CD8(+) T cells from OT-I/dnTGFβRII/Rag1(-/-) with CD4(+) T cells from OT-II/Rag1(-/-) mice failed to transfer disease.

CONCLUSION: Defective TGFβRII signaling, in addition to clonal CD8(+) T cells that target biliary cells, are required for induction of autoimmune cholangitis.