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The Natural Killer T (NKT) Cell Ligand -Galactosylceramide Demonstrates Its Immunopotentiating Effect by Inducing Interleukin (IL)-12 Production by Dendritic Cells and IL-12 Receptor Expression on NKT Cells

Hidemitsu Kitamura^*,, Kenji Iwakabe, Takashi Yahata, Shin-ichiro Nishimura, Akio Ohta^*, Yasushi Ohmi^*, Marimo Sato^*, Kazuyoshi Takeda^||, Ko Okumura^||, Luc Van Kaer^¶, Tetsu Kawano^**, Masaru Taniguchi^**, and Takashi Nishimura^*,

From the ^* Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, and Department of Immunology, Tokai University School of Medicine, Isehara 259-1193, Japan; the Division of Biological Sciences, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan; the ^|| Department of Immunology, Juntendo University School of Medicine, Tokyo 113-0033, Japan; the ^¶ Howard Hughes Medical Institute, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and ^** Core Research for Evolutional Science and Technology (CREST) Project and Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

The natural killer T (NKT) cell ligand -galactosylceramide (-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of -GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by -GalCer. We first established, using purified subsets of various lymphocyte populations, that -GalCer selectively activates NKT cells for production of interferon (IFN)-. Production of IFN- by NKT cells in response to -GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, -GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1^–/– or V14^–/– mice. This effect of -GalCer required the production of IFN- by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of -GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN- production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by -GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.

Key Words: natural killer T cells • dendritic cells • -galactosylceramide • interleukin 12 • interleukin 12 receptor

Abbreviations used: -GalCer, -galactosylceramide; DC, dendritic cell; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NKT, natural killer T; RT, reverse transcription.

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