The natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of α-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by α-GalCer. We first established, using purified subsets of various lymphocyte populations, that α-GalCer selectively activates NKT cells for production of interferon (IFN)-γ. Production of IFN-γ by NKT cells in response to α-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, α-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1−/− or Vα14−/− mice. This effect of α-GalCer required the production of IFN-γ by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of α-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-γ production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by α-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.
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5 April 1999
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April 05 1999
The Natural Killer T (NKT) Cell Ligand α-Galactosylceramide Demonstrates Its Immunopotentiating Effect by Inducing Interleukin (IL)-12 Production by Dendritic Cells and IL-12 Receptor Expression on NKT Cells
Hidemitsu Kitamura,
Hidemitsu Kitamura
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
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Kenji Iwakabe,
Kenji Iwakabe
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
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Takashi Yahata,
Takashi Yahata
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
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Shin-ichiro Nishimura,
Shin-ichiro 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
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Akio Ohta,
Akio Ohta
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
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Yasushi Ohmi,
Yasushi Ohmi
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
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Marimo Sato,
Marimo Sato
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
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Kazuyoshi Takeda,
Kazuyoshi Takeda
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
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Ko Okumura,
Ko Okumura
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
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Luc Van Kaer,
Luc Van Kaer
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
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Tetsu Kawano,
Tetsu Kawano
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
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Masaru Taniguchi,
Masaru Taniguchi
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
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Takashi Nishimura
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
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Hidemitsu Kitamura
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
Kenji Iwakabe
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
Takashi Yahata
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
Shin-ichiro 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
Akio Ohta
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
Yasushi Ohmi
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
Marimo Sato
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
Kazuyoshi Takeda
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
Ko Okumura
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
Luc Van Kaer
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
Tetsu Kawano
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
Masaru Taniguchi
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
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
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: [email protected]
Received:
November 09 1998
Revision Received:
January 21 1999
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1999
J Exp Med (1999) 189 (7): 1121–1128.
Article history
Received:
November 09 1998
Revision Received:
January 21 1999
Citation
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, Takashi Nishimura; The Natural Killer T (NKT) Cell Ligand α-Galactosylceramide Demonstrates Its Immunopotentiating Effect by Inducing Interleukin (IL)-12 Production by Dendritic Cells and IL-12 Receptor Expression on NKT Cells . J Exp Med 5 April 1999; 189 (7): 1121–1128. doi: https://doi.org/10.1084/jem.189.7.1121
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