title: Simulations of the NK cell immune synapse reveal that activation thresholds can be established by inhibitory receptors acting locally.
abstract: NK cell activation is regulated by a balance between activating and inhibitory signals. To address the question of how these signals are spatially integrated, we created a computer simulation of activating and inhibitory NK cell immunological synapse (NKIS) assembly, implementing either a "quantity-based" inhibition model or a "distance-based" inhibition model. The simulations mimicked the observed molecule distributions in inhibitory and activating NKIS and yielded several new insights. First, the total signal is highly influenced by activating complex dissociation rates but not by adhesion and inhibitory complex dissociation rates. Second, concerted motion of receptors in clusters significantly accelerates NKIS maturation. Third, when the potential of a cis interaction between Ly49 receptors and MHC class I on murine NK cells was added to the model, the integrated signal as a function of receptor and ligand numbers was only slightly increased, at least up to the level of 50% cis-bound Ly49 receptors reached in the model. Fourth, and perhaps most importantly, the integrated signal behavior obtained when using the distance-based inhibition signal model was closer to the experimentally observed behavior, with an inhibition radius of the order 3-10 molecules. Microscopy to visualize Vav activation in NK cells on micropatterned surfaces of activating and inhibitory strips revealed that Vav is only locally activated where activating receptors are ligated within a single NK cell contact. Taken together, these data are consistent with a model in which inhibitory receptors act locally; that is, that every bound inhibitory receptor acts on activating receptors within a certain radius around it.
authors.affiliation: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.
authors.forename: Asya
authors.initials: A
authors.lastname: Kaplan
authors.forename: Shulamit
authors.initials: S
authors.lastname: Kotzer
authors.forename: Catarina R
authors.initials: CR
authors.lastname: Almeida
authors.forename: Refael
authors.initials: R
authors.lastname: Kohen
authors.forename: Gilad
authors.initials: G
authors.lastname: Halpert
authors.forename: Mali
authors.initials: M
authors.lastname: Salmon-Divon
authors.forename: Karsten
authors.initials: K
authors.lastname: Köhler
authors.forename: Petter
authors.initials: P
authors.lastname: Höglund
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Davis
authors.forename: Ramit
authors.initials: R
authors.lastname: Mehr
mesh_terms: D000818:Animals; D003198:Computer Simulation; D006183:H-2 Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D054992:Immunological Synapses; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D021962:Membrane Microdomains / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D054340:Receptors, KIR / Q000378:metabolism
chemical_list: D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; D016169:Lymphocyte Function-Associated Antigen-1; C099187:MHC class I-related chain A; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055655:NK Cell Lectin-Like Receptor Subfamily K; D054340:Receptors, KIR; D018799:Intercellular Adhesion Molecule-1