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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. (Hepatology 2013;53:1094–1104)