title: Synergistic effect of KRN7000 with interleukin-15, -7, and -2 on the expansion of human V alpha 24+V beta 11+ T cells in vitro.
abstract: KRN7000, (2S, 3S, 4R)-1-O-(alpha-D-galactopyranosyl)-2-(N-hexacosanoylamino)-1, 3, 4-octadecanetriol, has been shown to prevent tumor metastasis to the liver through the activation of natural killer (NK) T cells in mice. In this study, the proliferation of human NK T cells, which express an invariant T cell antigen receptor (TCR) consisting of a Valpha24 chain and a Vbeta11 chain, was investigated using KRN7000, interleukin (IL)-15, IL-7, and IL-2 in vitro. KRN7000 stimulated the expansion of Valpha24(+)Vbeta11(+) T cells derived from peripheral blood mononuclear cells in a dose-dependent fashion, with some fluctuation between donors. IL-15, IL-7, and IL-2 synergistically stimulated the expansion of Valpha24(+)Vbeta11(+) T cells when combined with KRN7000. Intracellular expression of interferon (IFN)-gamma and IL-4 in Valpha24(+)Vbeta11(+) T cells expanded in the presence of KRN7000 was identified using flow cytometry. Valpha24(+)Vbeta11(+) T cells, expanded in the presence of KRN7000, contained granzyme (Gr) B-positive granules and perforin-positive granules. The addition of IL-15 to the culture containing KRN7000 increased GrB expression in Valpha24(+)Vbeta11(+) T cells while IL-7 and IL-2 failed to do it. In conclusion, the antitumor effect of KRN7000 may depend, in part, on granule-mediated cell killing through the activation of NK T cells and IL-15 may potentiate this effect.
authors.affiliation: Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Nishi
authors.forename: H J
authors.initials: HJ
authors.lastname: van der Vliet
authors.forename: Y
authors.initials: Y
authors.lastname: Koezuka
authors.forename: B M
authors.initials: BM
authors.lastname: von Blomberg
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002478:Cells, Cultured; D004357:Drug Synergism; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology*; D053804:Granzymes; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis; D015851:Interleukin-7 / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis*; D012697:Serine Endopeptidases / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D005699:Galactosylceramides; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D007378:Interleukins; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054353:Perforin; D015847:Interleukin-4; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C103873:KRN 7000