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

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.

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