Mechanisms of the antimetastatic effect in the liver and of the hepatocyte injury induced by α-galactosylceramide in mice

The role of mouse liver NK1.1 Ag+ T (NKT) cells in the antitumor effect of alpha -galactosylceramide (alpha -GalCer) has been unclear. We now show that, whereas alpha -GalCer increased the serum IFN-gamma concentration and alanine aminotransferase activity in NK cell-depleted C57BL/6 (B6) mice and B6-beige/beige mice similarly to its effects in control B6 mice, its enhancement of the antitumor cytotoxicity of liver mononuclear cells (MNCs) was abrogated. Depletion of both NK and NKT cells In B6 mice reduced all these effects of alpha -GalCer. Injection of Abs to IFN-gamma also inhibited the alpha -GalCer-induced increase in antitumor cytotoxicity of MNCs. alpha -GalCer induced the expression of Fas ligand on NKT cells in the liver of B6 mice. Whereas alpha -GalCer did not increase serum alanine aminotransferase activity in B6-lpr/lpr mice and B6-gld/gld mice, it increased the antitumor cytotoxicity of liver MNCs. The alpha -GalCer-induced increase in survival rate apparent in B6 mice injected intrasplenically with B16 tumor cells was abrogated in beige/beige mice, NK cell-depleted B6 mice, and B6 mice treated with Abs to IFN-gamma. Depletion of CD8(+) T cells did not affect the alpha -GalCer-induced antitumor cytotoxicity of liver MNCs but reduced the effect of alpha -GalCer on the survival of B6 mice. Thus, IFN-gamma produced by alpha -GalCer-activated NKT cells increases both the innate antitumor cytotoxicity of NK cells and the adaptive antitumor response of CD8(+) T cells, with consequent inhibition of tumor metastasis to the liver. Moreover, NKT cells mediate alpha -GalCer-induced hepatocyte injury through Fas-Fas ligand signaling.