Mechanisms of the antimetastatic effect in the liver and of the hepatocyteinjury induced by alpha-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 tha t, whereas alpha -GalCer increased the serum IFN-gamma concentration and al anine aminotransferase activity in NK cell-depleted C57BL/6 (B6) mice and B 6-beige/beige mice similarly to its effects in control B6 mice, its enhance ment of the antitumor cytotoxicity of liver mononuclear cells (MNCs) was ab rogated. Depletion of both NK and NKT cells In B6 mice reduced all these ef fects of alpha -GalCer. Injection of Abs to IFN-gamma also inhibited the al pha -GalCer-induced increase in antitumor cytotoxicity of MNCs. alpha -GalC er induced the expression of Fas ligand on NKT cells in the liver of B6 mic e. Whereas alpha -GalCer did not increase serum alanine aminotransferase ac tivity in B6-lpr/lpr mice and B6-gld/gld mice, it increased the antitumor c ytotoxicity of liver MNCs. The alpha -GalCer-induced increase in survival r ate apparent in B6 mice injected intrasplenically with B16 tumor cells was abrogated in beige/beige mice, NK cell-depleted B6 mice, and B6 mice treate d with Abs to IFN-gamma. Depletion of CD8(+) T cells did not affect the alp ha -GalCer-induced antitumor cytotoxicity of liver MNCs but reduced the eff ect of alpha -GalCer on the survival of B6 mice. Thus, IFN-gamma produced b y alpha -GalCer-activated NKT cells increases both the innate antitumor cyt otoxicity of NK cells and the adaptive antitumor response of CD8(+) T cells , with consequent inhibition of tumor metastasis to the liver. Moreover, NK T cells mediate alpha -GalCer-induced hepatocyte injury through Fas-Fas lig and signaling.