Study on the Role of CD8 T Cells in Xenobiotic Induced Primary Biliary Cirrhosis Murine Model
Date Issued
2012
Date
2012
Author(s)
Chen, Yu-Chi
Abstract
Primary biliary cirrhosis (PBC) is a liver-specific autoimmune disease with progressive destruction of intrahepatic bile ducts, decreased bile flow and destruction of hepatocytes, leading to scarring, fibrosis and then cirrhosis. In PBC patients, the number of autoantigen specific T cells in the liver is higher than in peripheral blood and CD8 T cells infiltration in the portal tracts is also present. Our lab previously established a murine model of PBC with xenobiotics (2-OA-BSA) /α-GalCer immunization The 2-OA-BSA/α-GalCer injected mice had an increased number of liver CD8 T cell numbers and developed PBC-like features such as liver lymphoid infiltration, portal inflammation, and fibrosis. In this study, we investigated the role of CD8 T cells in the pathogenesis of PBC.
First, we confirmed that the number of conventional T cells and CD8 T cells were increased in 2-OA-BSA /α-GalCer induced PBC mice and T cells infiltration in portal tracts were also observed. In addition, the secretion of IFN-γ and IL-17 from liver mononuclear cells (LMNCs) of PBC mice was increased. After adoptive transferring of T cells from PBC mice, increased serum levels of AMAs and secretion of IFN-γ of LMNC in recipients was noted. Further, we demonstrated that the frequency of IFN-γproducing liver CD8 T cells was higher than that of liver CD4 T cells. Moreover, CD8 T cells from PBC mice expressed higher CD69, FasL and granzyme B than in naive mice, suggesting that the CD8 T cells in PBC mice are activated and can be cytotoxic. We then adoptively transferred CD8 T cells from PBC mice into naive mice. Increased serum levels of AMAs and secretion of IFN-γ from LMNC of recipients were also obeserved, which was similar to the results of mice transferred with total T cells.
However, CD8 deficient (CD8-/-) mice immunized with 2-OA-BSA /α-GalCer developed AMAs in serum, IFN-γ secretion of LMNC, liver portal infiltration and fibrosis like the characteristics in wild type mice. Additionally, we found γδ T cells were expanded in CD8-/- PBC mice and possessed cytotoxic potential, suggesting γδ T cells might be pathogenic in CD8-/- PBC mice.
In conclusion, our data suggested that CD8 T cells in 2-OA-BSA /α-GalCer induced PBC mice were hyperreactive and cytotoxic, and that these cells directly or indirectly induced lesions of PBC. In addition, γδ T cells might replace the pathogenesis role of CD8 T cells when CD8 T cells are deficient.
Subjects
Primary Biliary Cirrhosis
CD8 T cell
gamma delta T cell
Type
thesis
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