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

Ryusuke Nakagawa^*, Takuo Inui, Ikuko Nagafune, Yoshiko Tazunoki, Kazuhiro Motoki, Akira Yamauchi^*, Mitsuomi Hirashima, Yoshiko Habu, Hiroyuki Nakashima and Shuhji Seki^1,

Departments of ^* Cell Regulation and Immunology and Immunopathology, Kagawa Medical University, Kagawa, Japan; Department of Microbiology, National Defense Medical College, Tokorozawa, Japan; and Pharmaceutical Research Laboratory, Kirin Brewery, Takasaki, Japan

We recently reported that NK cells and CD8⁺ T cells contribute to the antimetastatic effect in the liver induced by -galactosylceramide (-GalCer). In the present study, we further investigated how CD8⁺ T cells contribute to the antimetastatic effect induced by -GalCer. The injection of anti-CD8 Ab into mice 3 days before -GalCer injection (2 days before intrasplenic injection of B16 tumors) did not inhibit IFN- production nor did it reduce the NK activity of liver mononuclear cells after -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 -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 -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/-GalCer injection for the mice to generate CD8⁺ T cells that can reject s.c. rechallenged B16 cells. These findings suggest that -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.

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