Essential role of bystander cytotoxic CD122+CD8+ T cells for the antitumor immunity induced in the liver of mice by alpha-galactosylceramide

J Immunol. 2004 Jun 1;172(11):6550-7. doi: 10.4049/jimmunol.172.11.6550.

Abstract

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.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Cytotoxicity, Immunologic*
  • Galactosylceramides / pharmacology*
  • Immunologic Memory
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology
  • Liver / immunology*
  • Lymphocyte Activation
  • Melanoma, Experimental / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Interleukin-2 / analysis*
  • Receptors, Interleukin-2 / physiology
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Galactosylceramides
  • Receptors, Interleukin-2
  • Interferon-gamma