Essential Role of Bystander Cytotoxic CD122+CD8+ T Cells for the Antitumor Immunity Induced in the Liver of Mice by α-Galactosylceramide

We recently reported that NK cells and CD8 + T cells contribute to the antimetastatic effect in the liver induced by α-galactosylceramide (α-GalCer). In the present study, we further investigated how CD8 + T cells contribute to the antimetastatic effect induced by α-GalCer. The injection of anti-CD8 Ab into mice 3 days before α-GalCer injection (2 days before intrasplenic injection of B16 tumors) did not inhibit IFN-γ production nor did it reduce the NK activity of liver mononuclear cells after α-GalCer stimulation. However, it did cause a reduction in the proliferation of liver mononuclear cells and mouse survival time. Furthermore, although the depletion of NK and NKT cells (by anti-NK1.1 Ab) 2 days after α-GalCer injection no longer decreased the survival rate of B16 tumor-injected mice, the depletion of CD8 + T cells did. CD122 + CD8 + T cells in the liver increased after α-GalCer injection, and antitumor cytotoxicity of CD8 + T cells in the liver gradually increased until day 6. These CD8 + T cells exhibited an antitumor cytotoxicity toward not only B16 cells, but also EL-4 cells, and their cytotoxicity significantly decreased by the depletion of CD122 + CD8 + T cells. The critical, but bystander role of CD122 + CD8 + T cells was further confirmed by adoptive transfer experiments into CD8 + T cell-depleted mice. Furthermore, it took 14 days after the first intrasplenic B16/α-GalCer injection for the mice to generate CD8 + T cells that can reject s.c. rechallenged B16 cells. These findings suggest that α-GalCer activates bystander antitumor CD122 + CD8 + T cells following NK cells and further induces an adaptive antitumor immunity due to tumor-specific memory CD8 + CTLs.