[1, 2] We have demonstrated that PDC-E2, along with other mitochondrial autoantigens, are present within the apoptotic blebs from human intrahepatic biliary epithelial cells (HiBECs), but not detected in apoptotic blebs from other human tissues.[21, 22] We have also demonstrated that PDC-E2-specific autoreactive CD4+ and CD8+ T cells exist in peripheral blood and are highly enriched in the liver of PBC patients.[14-17, 23] Taken together, these data suggest that autoreactive T cells play a critical role in the tissue-specific immunopathogenesis of PBC. In addition to these studies based on human clinical specimens, we have used the dnTGFβRII mice with TGFβ signaling
Talazoparib mouse deficiency in the T cells, a mouse model of autoimmune Roxadustat research buy cholangitis that resembles human PBC, to demonstrate that the CD8+ cytotoxic T-cell population with the impaired TGFβ signaling is essential for the development of autoimmune biliary epithelial damage in this model. However, it is unclear whether the pathogenic CD8+ T cells in the liver of dnTGFβRII mice require antigen specificity. To examine the role of antigen specificity in the T-cell-mediated autoimmune cholangitis in the dnTGFβRII mice, we generated two mouse strains, OT-I/dnTGFβRII/Rag1−/− and OT-II/dnTGFβRII/Rag1−/−, in which the entire T-cell repertoire was replaced with either CD8+ or CD4+ T cells specific for
a single irrelevant antigen OVA. We demonstrated that OT-II/dnTGFβRII/Rag1−/−
mice had no inflammation in liver at 24 weeks of age, while the OT-I/dnTGFβRII/Rag1−/− mice had minimal inflammation in portal tract but no autoimmune cholangitis. We further demonstrated that adoptive transfer of CD8+ T cells from OT-I/dnTGFβRII/Rag1−/− mice did not induce cholangitis in the recipient mice. A previous study demonstrated that MCE Rag1−/− recipient mice transferred with CD8+ T cell from Tgfbr2f/f dLcK-Cre mice plus CD4+ T cell from control mice developed more severe autoimmunity compared to the recipients of Tgfbr2f/f dLcK-Cre CD8+ T cells alone. Indeed, isolated CD8+ T cells from OT-I/dnTGFβRII/Rag1−/− had not received CD4+ T cell help during development, while isolated CD8+ T cells from dnTGFβRII had received CD4+ T cell help during development. In addition, consequently, we confirmed that adoptive transfer of CD8+ T cells from OT-I/dnTGFβRII/Rag1−/− mice with CD4+ T cells from OT-II/dnTGFβRII/Rag1−/− mice did not induce cholangitis in recipient mice. We also showed that the TGFβ signaling defect had the same effect on the OT-I/dnTGFβRII/Rag1−/− peripheral CD8 cells as on dnTGFβRII cells—i.e., excess accumulation (higher cell numbers), spontaneous activation (increased CD44), and excessive cytokine production (increased Th1 cytokines). Despite these abnormalities, these cells did not mediate disease upon transfer, nor did they produce excess cytokines without CD4 help.