Innate Vα14+ natural killer T cells mature dendritic cells, leading to strong adaptive immunity

Authors

  • Shin-Ichiro Fujii,

    1. Research Unit for Cellular Immunotherapy, Research Center for Allergy and Immunology (RCAI), RIKEN, Yokohama, Kanagawa, Japan.
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  • Kanako Shimizu,

    1. Research Unit for Cellular Immunotherapy, Research Center for Allergy and Immunology (RCAI), RIKEN, Yokohama, Kanagawa, Japan.
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  • Hiroaki Hemmi,

    1. Laboratory of Cellular Physiology and Immunology and Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA.
    2. Medical Top Track (MTT) Program, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
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  • Ralph M. Steinman

    1. Laboratory of Cellular Physiology and Immunology and Christopher H. Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, NY, USA.
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Ralph M. Steinman
Laboratory of Cellular Physiology and Immunology and Christopher H. Browne Center for Immunology and Immune Diseases
The Rockefeller University
1230 York Avenue
New York, NY 10021-6399, USA.
Tel.: +1 212 327 8106
Fax: +1 212 327 8875
e-mail: steinma@rockefeller.edu

Abstract

Summary: The observation that the glycolipid α-galactosylceramide (α-GalCer) is a potent stimulator of natural killer T (NKT) cells has provided an important means for investigating NKT cell biology. α-GalCer is presented on CD1d to the invariant NKT receptor, leading to interleukin-12 (IL-12) production by dendritic cells (DCs) and to NK cell activation. We review our research on the tumor-protective properties of α-GalCer, particularly the major role played by DCs. We compared administration of α-GalCer on mature DCs with soluble glycolipid and found that DCs induced more prolonged interferon-γ (IFN-γ) production by NKT cells and better protection against B16 melanoma. Human α-GalCer-loaded DCs also expanded NKT cell numbers in cancer patients. α-GalCer-activated NKT cells were then found to induce DC maturation in vivo. The maturing DCs produced IL-12, upregulated co-stimulatory molecules, and induced adaptive immunity to captured cellular antigens, including prolonged, combined CD4+/CD8+ T-cell immunity to dying tumor cells. Surprisingly, co-stimulator-poor tumor cells, if directly loaded with α-GalCer (‘tumor/Gal’) and injected intravenously, also induced strong NKT- and NK-cell responses. The latter killed the tumor/Gal, which were subsequently cross presented by CD1d on DCs to elicit DC maturation and prolonged adaptive T-cell immunity, which lasted 6–12 months. These findings help explain tumor protection via α-GalCer and urge development of the DC-NKT axis to provide innate and adaptive immunity to human cancers.

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