title: Innate Valpha14(+) natural killer T cells mature dendritic cells, leading to strong adaptive immunity.
abstract: The observation that the glycolipid alpha-galactosylceramide (alpha-GalCer) is a potent stimulator of natural killer T (NKT) cells has provided an important means for investigating NKT cell biology. alpha-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 alpha-GalCer, particularly the major role played by DCs. We compared administration of alpha-GalCer on mature DCs with soluble glycolipid and found that DCs induced more prolonged interferon-gamma (IFN-gamma) production by NKT cells and better protection against B16 melanoma. Human alpha-GalCer-loaded DCs also expanded NKT cell numbers in cancer patients. alpha-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 alpha-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 alpha-GalCer and urge development of the DC-NKT axis to provide innate and adaptive immunity to human cancers.
authors.affiliation: Research Unit for Cellular Immunotherapy, Research Center for Allergy and Immunology (RCAI), RIKEN, Yokohama, Kanagawa, Japan.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Fujii
authors.forename: Kanako
authors.initials: K
authors.lastname: Shimizu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hemmi
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
mesh_terms: D000818:Animals; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology*; D005699:Galactosylceramides / Q000032:analysis / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D005699:Galactosylceramides; D015395:Histocompatibility Antigens Class I; C493154:alpha-galactosylceramide; D007371:Interferon-gamma