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© The Rockefeller University Press, 0022-1007/1999/4/1121/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 7, April 5, 1999 1121-1128

Articles

The Natural Killer T (NKT) Cell Ligand {alpha}-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{ddagger}, Takashi Yahata{ddagger}, Shin-ichiro Nishimura§, Akio Ohta*, Yasushi Ohmi*, Marimo Sato*, Kazuyoshi Takeda||, Ko Okumura||, Luc Van Kaer, Tetsu Kawano**, Masaru Taniguchi**, and Takashi Nishimura*,{ddagger}

From the * Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, and {ddagger} 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 {alpha}-galactosylceramide ({alpha}-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of {alpha}-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by {alpha}-GalCer. We first established, using purified subsets of various lymphocyte populations, that {alpha}-GalCer selectively activates NKT cells for production of interferon (IFN)-{gamma}. Production of IFN-{gamma} by NKT cells in response to {alpha}-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, {alpha}-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1–/– or V{alpha}14–/– mice. This effect of {alpha}-GalCer required the production of IFN-{gamma} by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of {alpha}-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-{gamma} production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by {alpha}-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 • {alpha}-galactosylceramide • interleukin 12 • interleukin 12 receptor

Address correspondence to Takashi Nishimura, Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, Department of Immunology, Tokai University School of Medicine, Bohseidai, Isehara 259-1193, Japan. Phone: 81-463-93-1121; Fax: 81-463-96-5438; E-mail: tak24{at}is.icc.u-tokai.ac.jp

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


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