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

Abstract

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.