title: Gap junction intercellular communications regulate NK cell activation and modulate NK cytotoxic capacity.
abstract: Gap junctions (GJs) mediate intercellular communication between adjacent cells. Previously, we showed that connexin 43 (Cx43), the main GJ protein in the immune system, mediates Ag transfer between human dendritic cells (DCs) and is recruited to the immunological synapse during T cell priming. This crosstalk contributed to T cell activation, intracellular Ca(2+) responses, and cytokine release. However, the role of GJs in NK cell activation by DCs and NK cell-mediated cytotoxicity against tumor cells remains unknown. In this study, we found polarization of Cx43 at the NK/DC and NK/tumor cell-contact sites, accompanied by the formation of functional GJs between NK/DCs and NK/tumor cells, respectively. Cx43-GJ-mediated intercellular communication (GJIC) between human NK and DCs was bidirectional. Blockage of Cx43-GJIC inhibited NK cell activation, though it affected neither the phenotype nor the function of DCs. Cx43 knockdown or inhibition using mimetic peptides greatly reduced CD69 and CD25 expression and IFN-γ release by DC-stimulated NK cells. Moreover, blocking Cx43 strongly inhibited the NK cell-mediated tumor cell lysis associated with inhibition of granzyme B activity and Ca(2+) influx. Our data identify a novel and active role for Cx43-GJIC in human NK cell activation and antitumor effector functions that may be important for the design of new immune therapeutic strategies.
authors.affiliation: Faculty of Medicine, Institute of Biomedical Sciences, University of Chile, 8380453 Santiago, Chile;
authors.forename: Andrés
authors.initials: A
authors.lastname: Tittarelli
authors.forename: Ariadna
authors.initials: A
authors.lastname: Mendoza-Naranjo
authors.forename: Marcela
authors.initials: M
authors.lastname: Farías
authors.forename: Israel
authors.initials: I
authors.lastname: Guerrero
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ihara
authors.forename: Erik
authors.initials: E
authors.lastname: Wennerberg
authors.forename: Sebastian
authors.initials: S
authors.lastname: Riquelme
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gleisner
authors.forename: Alexis
authors.initials: A
authors.lastname: Kalergis
authors.forename: Andreas
authors.initials: A
authors.lastname: Lundqvist
authors.forename: Mercedes N
authors.initials: MN
authors.lastname: López
authors.forename: Benedict J
authors.initials: BJ
authors.lastname: Chambers
authors.forename: Flavio
authors.initials: F
authors.lastname: Salazar-Onfray
mesh_terms: D017209:Apoptosis; D020013:Calcium Signaling; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000648:ultrastructure; D017629:Gap Junctions / Q000276:immunology*; D053804:Granzymes / Q000502:physiology; D006801:Humans; D007157:Immunologic Surveillance; D054992:Immunological Synapses / Q000276:immunology; D059425:Interferon-gamma Release Tests; D007694:Killer Cells, Natural / Q000276:immunology* / Q000648:ultrastructure; D008213:Lymphocyte Activation / Q000276:immunology*
chemical_list: D018031:Connexin 43; C500216:GJA1 protein, human; C509213:GZMB protein, human; D053804:Granzymes