Essential role of bystander cytotoxic CD122+CD8+ T cells for the antitumor immunity induced in the liver of mice by alpha-galactosylceramide.
We recently reported that NK cells and CD8(+) T cells contribute to the antimetastatic effect in the liver induced by alpha-galactosylceramide (alpha-GalCer). In the present study, we further investigated how CD8(+) T cells contribute to the antimetastatic effect induced by alpha-GalCer. The injection of anti-CD8 Ab into mice 3 days before alpha-GalCer injection (2 days before intrasplenic injection of B16 tumors) did not inhibit IFN-gamma production nor did it reduce the NK activity of liver mononuclear cells after alpha-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 alpha-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 alpha-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/alpha-GalCer injection for the mice to generate CD8(+) T cells that can reject s.c. rechallenged B16 cells. These findings suggest that alpha-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.
Nakagawa
Ryusuke
R
Department of Cell Regulation, Kagawa Medical University, Kagawa, Japan.
Inui
Takuo
T
Nagafune
Ikuko
I
Tazunoki
Yoshiko
Y
Motoki
Kazuhiro
K
Yamauchi
Akira
A
Hirashima
Mitsuomi
M
Habu
Yoshiko
Y
Nakashima
Hiroyuki
H
Seki
Shuhji
S
D019264:Adoptive Transfer; D000818:Animals; D003602:Cytotoxicity, Immunologic; D005699:Galactosylceramides / Q000494:pharmacology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000276:immunology*; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000032:analysis* / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D005699:Galactosylceramides; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma