title: Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15.
abstract: Recombinant adenovirus-engineered dendritic cells (Ad.DCs) are potent immunologic adjuvants of antiviral and anticancer vaccines. The effectiveness of Ad.DC-based vaccines may depend on the ability of Ad.DCs to crosstalk with natural killer (NK) cells and to activate, polarize, and bridge innate and adaptive immunity. We investigated, for the first time, whether and how human Ad.DCs activate NK cells, and compared the Ad.DC function with that of immature DCs and matured DCs (mDCs). We found that adenovirus transduction and lipopolysaccharide/interferon-gamma-induced maturation increased expression of transmembrane tumor necrosis factor (TNF) and trans-presented (trans) interleukin-15 (IL-15) on DCs, leading to enhanced NK cell activation without enhancing DC susceptibility to NK cell-mediated killing. This crosstalk enhanced NK cell CD69 expression, interferon-gamma secretion, proliferation, and antitumor activities, with Ad.DCs being significantly more effective than immature DCs, but less effective than mDCs. The Ad.DC and mDC crosstalk with NK cells was largely prevented by physical separation of DCs and NK cells, and neutralization of total TNF and IL-15, but not by selective sequestration of soluble TNF. These findings demonstrate that both Ad.DCs and mDCs can efficiently promote innate immune functions by activation of NK cells through the cooperative activities of tmTNF and trans-IL-15 mediated by cell-to-cell contact.
authors.affiliation: Department of Pathology and Immunology, University of Pittsburgh, Hillman Cancer Center, 5117 Centre Ave., Pittsburgh, PA 15213, USA.
authors.forename: Lazar
authors.initials: L
authors.lastname: Vujanovic
authors.forename: David E
authors.initials: DE
authors.lastname: Szymkowski
authors.forename: Sean
authors.initials: S
authors.lastname: Alber
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Nikola L
authors.initials: NL
authors.lastname: Vujanovic
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
mesh_terms: D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology* / Q000821:virology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011485:Protein Binding / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
chemical_list: D019409:Interleukin-15; D014409:Tumor Necrosis Factor-alpha