Natural Killer T Cells Exacerbate Liver Injury in a Transforming Growth Factor Beta Receptor Ii Dominant-Negative Mouse Model of Primary Biliary Cirrhosis
Resource
HEPATOLOGY v.47 n.2 pp.571-580
Journal
HEPATOLOGY
Journal Volume
v.47
Journal Issue
n.2
Pages
571-580
Date Issued
2008
Date
2008
Author(s)
CHUANG, YA-HUI
Abstract
Primary biliary cirrhosis (PBC) is an organ-specific autoinumme liver disease characterized by the presence of antimitochondrial antibodies and the destruction of small intrahepatic bile ducts with portal inflammation. In previous studies, we reported that both CD1d expression and the frequency of CD1d-restricted natural killer T (NKT) cells were increased in the livers of patients with PBC. To define a specific role of CD1d- restricted NKT cells in the pathogenesis of PBC, particularly early events , we investigated the function of hepatic CD1d-restricted NK-T cells in our transforming growth factor P (TGF-beta) receptor II dominant-negative (dnTGF beta RII) mouse model of PBC. We generated CD1d(-/-) and CD1d(-/-) dnTGF beta RII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGF beta RII mice demonstrate a massive increase of hyperactive CD1d- restricted NKT cells within the hepatic tissues. CD1d(-/-) dnTGF beta RII mice, which lack CD1d -restricted CD1d- restricted NKT cells, exhibit significantly decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1 d(-/-)dnTGF beta RII mice. Interestingly, there was a significant increase in the production of interferon-gamma in hepatic CD1d-restricted NKT cells activated by a-galactosylceramide in young but not older dnTGF beta RII mice, suggesting an age-dependent role of CD1 d-restricted NKT cells. Conclusion: These data demonstrate that CD1d-restricted NKT cells in dnTGF beta RII mice are a critical factor in liver injury.