title: Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT.
abstract: Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell-sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self-MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14-dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues.
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom; and.
authors.forename: Tim D
authors.initials: TD
authors.lastname: Holmes
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom; and.
authors.forename: Erica B
authors.initials: EB
authors.lastname: Wilson
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom; and.
authors.forename: Emma V I
authors.initials: EV
authors.lastname: Black
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom; and.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Benest
authors.affiliation: Bioinformatics Institute and.
authors.forename: Candida
authors.initials: C
authors.lastname: Vaz
authors.affiliation: Bioinformatics Institute and.
authors.forename: Betty
authors.initials: B
authors.lastname: Tan
authors.affiliation: Bioinformatics Institute and Institute of Medical Biology, A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore 138671.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Tanavde
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds School of Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom; and g.p.cook@leeds.ac.uk.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Cook
mesh_terms: D002450:Cell Communication / Q000276:immunology*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance; D019409:Interleukin-15 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D009369:Neoplasms / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000276:immunology*
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C569274:IL15 protein, human; C508594:IL2 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D017452:Receptors, IgG; C505914:TNFSF14 protein, human; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14
keywords: NK-cell licensing; NK–DC interactions; TNFSF14; natural killer cells; tumor immunity