title: NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1.
abstract: Interaction of natural killer (NK) cells with autologous immature dendritic cells (DCs) results in reciprocal activation; however, the underlying mechanisms are so far elusive. We show here that NK cells trigger immature DCs to polarize and secrete interleukin 18 (IL-18), a cytokine lacking a secretory leader sequence. This occurs through a Ca2+-dependent and tubulin-mediated recruitment of IL-18-containing secretory lysosomes toward the adhering NK cell. Lysosome exocytosis and IL-18 secretion are restricted at the synaptic cleft, thus allowing activation of the interacting NK cells without spreading of the cytokine. In turn, DC-activated NK cells secrete the proinflammatory cytokine high mobility group B1 (HMGB1), which induces DC maturation and protects DCs from lysis. Also HMGB1 is a leaderless cytokine that undergoes regulated secretion. Differently from IL-18, soluble HMGB1 is consistently detected in NK/DC supernatants. These data point to secretion of leaderless cytokines as a key event for the reciprocal activation of NK cells and DCs. DCs initiate NK cell activation by targeted delivery of IL-18, thus instructing NK cells in the absence of adaptive-type cytokines; in turn, activated NK cells release HMGB1, which promotes inflammation and induces DC maturation, thus favoring the onset of the adaptive immune response.
authors.affiliation: Laboratory of Cell Biology, Department of Translational Oncology, National Institute for Cancer Research, Largo Rosanna Benzi, 10, 16132 Genova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Semino
authors.forename: Giovanna
authors.initials: G
authors.lastname: Angelini
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
mesh_terms: D020013:Calcium Signaling; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation; D016764:Cell Polarity; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D024243:HMGB1 Protein / Q000096:biosynthesis*; D006801:Humans; D066298:In Vitro Techniques; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D020382:Interleukin-18; D011994:Recombinant Proteins; D014404:Tubulin