title: Effects of alpha-galactosylceramide (KRN7000), interleukin-12 and interleukin-7 on phenotype and cytokine profile of human Valpha24+ Vbeta11+ T cells.
abstract: The alpha-galactosylceramide KRN7000 was reported to be presented by CD1d to natural killer (NK) T cells, cells that are thought to play an important role in the rejection of malignant tumours and in the regulation of several autoimmune diseases. Here we analysed human peripheral blood (PB) NK T cells (Valpha24+ Vbeta11+ T cells) before and after a short-term culture in the presence of KRN7000. KRN7000 strongly activated PB Valpha24+ Vbeta11+ T cells and, when stimulated, the vast majority of these cells expressed interferon-gamma (IFN-gamma). Exposure of these KRN7000-cultured Valpha24+ Vbeta11+ T cells to interleukin-12 (IL-12), but not to IL-7, resulted in a relative increase in IFN-gamma-expressing Valpha24+ Vbeta11+ T cells, compared with IL-4-expressing Valpha24+ Vbeta11+ T cells, indicating a shift towards a T-helper type 1 (Th1) phenotype. KRN7000 strongly up-regulated the expression of the cytotoxic molecule granzyme B (GrB) in Valpha24+ Vbeta11+ T cells. Although IL-7 resulted in a decrease in GrB levels in KRN7000-cultured Valpha24+ Vbeta11+ T cells, IL-12 increased GrB levels in both Valpha24+ Vbeta11+ T cells and in Valpha24+ Vbeta11+ T-cell clones and increased cytotoxicity against hCD1d-transfected HeLa cells. Our data provide further insight into the characteristics of human Valpha24+ Vbeta11+ T cells and indicate that KRN7000 is a potent activator of Valpha24+ Vbeta11+ T cells. Combined with the established anti-tumour effects of KRN7000 in mouse models, these results may support the use of KRN7000 as an anti-tumour agent in man.
authors.affiliation: Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: H J
authors.initials: HJ
authors.lastname: Van Der Vliet
authors.forename: N
authors.initials: N
authors.lastname: Nishi
authors.forename: Y
authors.initials: Y
authors.lastname: Koezuka
authors.forename: M A
authors.initials: MA
authors.lastname: Peyrat
authors.forename: B M
authors.initials: BM
authors.lastname: Von Blomberg
authors.forename: A J
authors.initials: AJ
authors.lastname: Van Den Eertwegh
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
authors.forename: R J
authors.initials: RJ
authors.lastname: Scheper
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D002999:Clone Cells; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005699:Galactosylceramides / Q000494:pharmacology*; D053804:Granzymes; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology; D015851:Interleukin-7 / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D012697:Serine Endopeptidases / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D005699:Galactosylceramides; D015851:Interleukin-7; D007476:Ionophores; D018664:Interleukin-12; D015847:Interleukin-4; D000001:Calcimycin; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases; D013755:Tetradecanoylphorbol Acetate; C103873:KRN 7000