title: Natural killer cell signal integration balances synapse symmetry and migration.
abstract: Natural killer (NK) cells discern the health of other cells by recognising the balance of activating and inhibitory ligands expressed by each target cell. However, how the integration of activating and inhibitory signals relates to formation of the NK cell immune synapse remains a central question in our understanding of NK cell recognition. Here we report that ligation of LFA-1 on NK cells induced asymmetrical cell spreading and migration. In contrast, ligation of the activating receptor NKG2D induced symmetrical spreading of ruffled lamellipodia encompassing a dynamic ring of f-actin, concurrent with polarization towards a target cell and a "stop" signal. Ligation of both LFA-1 and NKG2D together resulted in symmetrical spreading but co-ligation of inhibitory receptors reverted NK cells to an asymmetrical migratory configuration leading to inhibitory synapses being smaller and more rapidly disassembled. Using micropatterned activating and inhibitory ligands, signals were found to be continuously and locally integrated during spreading. Together, these data demonstrate that NK cells spread to form large, stable, symmetrical synapses if activating signals dominate, whereas asymmetrical migratory "kinapses" are favoured if inhibitory signals dominate. This clarifies how the integration of activating and inhibitory receptor signals is translated to an appropriate NK cell response.
authors.affiliation: Division of Cell and Molecular Biology, Imperial College London, London, United Kingdom.
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Culley
authors.forename: Matthew
authors.initials: M
authors.lastname: Johnson
authors.forename: J Henry
authors.initials: JH
authors.lastname: Evans
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.forename: Rupert
authors.initials: R
authors.lastname: Crilly
authors.forename: Juan
authors.initials: J
authors.lastname: Casasbuenas
authors.forename: Tim
authors.initials: T
authors.lastname: Schnyder
authors.forename: Maryam
authors.initials: M
authors.lastname: Mehrabi
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Deonarain
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Ushakov
authors.forename: Veronique
authors.initials: V
authors.lastname: Braud
authors.forename: Günter
authors.initials: G
authors.lastname: Roth
authors.forename: Roland
authors.initials: R
authors.lastname: Brock
authors.forename: Karsten
authors.initials: K
authors.lastname: Köhler
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Davis
mesh_terms: D000199:Actins / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002469:Cell Separation; D002478:Cells, Cultured; D054992:Immunological Synapses / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014162:Transfection
chemical_list: D000199:Actins; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1