Natural killer T cells exacerbate liver injury in a transforming growth factor β receptor II dominant-negative mouse model of primary biliary cirrhosis

Authors

  • Ya-Hui Chuang,

    1. Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA
    2. Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China
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    • These authors contributed equally to the study.

  • Zhe-Xiong Lian,

    Corresponding author
    1. Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA
    • Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 E. Health Sciences Drive, Suite 6510, Davis, CA 95616
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    • These authors contributed equally to the study.

    • fax: 530-752-4669

  • Guo-Xiang Yang,

    1. Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • Shang-An Shu,

    1. Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • Yuki Moritoki,

    1. Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • William M. Ridgway,

    1. Division of Rheumatology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Aftab A. Ansari,

    1. Department of Pathology, Emory University School of Medicine, Atlanta, GA
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  • Mitchell Kronenberg,

    1. La Jolla Institute of Allergy and Immunology, La Jolla, CA
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  • Richard A. Flavell,

    1. Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT
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  • Bin Gao,

    1. Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
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  • M. Eric Gershwin

    1. Division of Rheumatology/Allergy and Clinical Immunology, University of California at Davis, Davis, CA
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  • Potential conflict of interest: Nothing to report.

Abstract

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune 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 NKT cells in our transforming growth factor β (TGF-β) receptor II dominant-negative (dnTGFβRII) mouse model of PBC. We generated CD1d−/− and CD1d+/− dnTGFβRII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGFβRII mice demonstrate a massive increase of hyperactive CD1d-restricted NKT cells within the hepatic tissues. CD1d−/−dnTGFβRII mice, which lack CD1d-restricted CD1d-restricted NKT cells, exhibit significantly decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1d+/−dnTGFβRII mice. Interestingly, there was a significant increase in the production of interferon-γ in hepatic CD1d-restricted NKT cells activated by α-galactosylceramide in young but not older dnTGFβRII mice, suggesting an age-dependent role of CD1d-restricted NKT cells. Conclusion: These data demonstrate that CD1d-restricted NKT cells in dnTGFβRII mice are a critical factor in liver injury. (HEPATOLOGY 2008.)

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