Critical contribution of IFN-gamma and NK cells, but not perforin-mediated cytotoxicity, to anti-metastatic effect of alpha-galactosylceramide.

Hayakawa Y, Takeda K, Yagita H, Kakuta S, Iwakura Y, Van Kaer L, Saiki I, Okumura K
Eur J Immunol. 2001 31 (6): 1720-7

PMID: 11385616

The glycolipid alpha -galactosylceramide (alpha -GalCer), which is presented by CD1d and specifically activates Valpha 14 NKT cells, exerts a potent anti-metastatic effect when administered in vivo. In this study, we demonstrated that alpha -GalCer administration led to rapid elimination of NKT cells by apoptosis in the liver and spleen, after they produced IFN-gamma and IL-4. In contrast, a more prolonged secretion of IFN-gamma was observed by liver and splenic NK cells after alpha -GalCer administration. Cytotoxic activity of liver mononuclear cells was not augmented 3h after alpha -GalCer administration, but was increased at 24 h when NKT cells were mostly depleted. The alpha -GalCer-induced cytotoxic activity was abolished in IFN-gamma -deficient and NK cell-depleted mice as well as CD1-deficient mice, suggesting that the alpha -Galcer-induced cytotoxicity was mainly mediated by IFN-gamma -activated NK cells. While the alpha -GalCer-induced cytotoxicity in vitro was mostly perforin dependent, anti-metastatic effect of alpha -GalCer was impaired in NK cell-depleted or IFN-gamma -deficient mice but not in perforin-deficient mice. Collectively, these results indicated that the anti-metastatic effect of alpha -GalCer is mainly mediated by NK cells, which are activated secondarily by IFN-gamma produced by alpha -GalCer-activated NKT cells, in a perforin-independent manner.

MeSH Terms (17)

Animals Antineoplastic Agents Apoptosis Cytotoxicity, Immunologic Galactosylceramides Interferon-gamma Interleukin-4 Killer Cells, Natural Lymphocyte Activation Membrane Glycoproteins Mice Mice, Inbred C57BL Neoplasm Metastasis Perforin Pore Forming Cytotoxic Proteins T-Lymphocytes Time Factors

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