Activated natural killer T cells producing interferon-gamma elicit promoting activity to murine dendritic cell-based autoimmune hepatic inflammation

Authors

  • M. Nakano,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
    2. Department of Oncology, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo, Japan
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  • C. Saeki,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
    2. Department of Oncology, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo, Japan
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  • H. Takahashi,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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  • S. Homma,

    Corresponding author
    1. Department of Oncology, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo, Japan
    • Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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  • H. Tajiri,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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  • M. Zeniya

    1. Gastroenterology, Jikei University School of Medicine, Tokyo, Japan
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Correspondence: S. Homma, Department of Oncology, Institute of DNA Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo 105-8461, Japan.

E-mail: sahya@jikei.ac.jp

Summary

As natural killer (NK) T cells play an important role in the development of autoimmune diseases, they should have significant roles for the pathogenesis of autoimmune liver disease. Implication of the NK T cells in the generation of autoimmune-related hepatic inflammation was investigated using a novel mouse model. Immunization of mice with dendritic cells (DCs) loaded with hepatocyte-mimicking hepatocellular carcinoma cells (DC/Hepa1-6) induces cytotoxic T lymphocytes (CTL) capable of killing hepatocytes. Subsequent administration of interleukin (IL)-12, a potent interferon-gamma (IFN-γ) inducer, to the immunized mice generates autoimmune hepatic inflammation (AHI), as reported previously. Upon onset of the AHI response, the number of intrahepatic CD3+NK1·1+ NK T cells increased markedly, along with a decrease in the number of splenic NK T cells, augmented expression of CXCR6 on intrahepatic NK T cells and CXCL16 in hepatic tissue, suggesting that NK T cells were recruited into the inflamed liver. The NK T cells were strongly positive for CD69 and produced IFN-γ, but not IL-4. AHI activity was attenuated markedly in CD1d–/– NK T cell-deficient mice, indicating that NK T cells play a pivotal role in the development of AHI. Mice treated with DC/Hepa1-6 and alpha-galactosylceramide, a potent NK T cell activator, also exhibited similar hepatic inflammation, in which activated NK T cells producing IFN-γ and CD8+ T cells cytotoxic to hepatocytes were induced in liver-infiltrating mononuclear cells. Activated NK T cells producing IFN-γ potentiate DC-based AHI in the mouse model.

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