{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T16:15:08Z","timestamp":1770912908488,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010114","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000}}],"reference-count":92,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T00:00:00Z","timestamp":1652832000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-AI 143740"],"award-info":[{"award-number":["R01-AI 143740"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-AI 146581"],"award-info":[{"award-number":["R01-AI 146581"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Nationwide Children\u2019s Hospital"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Natural Killer (NK) cells provide key resistance against viral infections and tumors. A diverse set of activating and inhibitory NK cell receptors (NKRs) interact with cognate ligands presented by target host cells, where integration of dueling signals initiated by the ligand-NKR interactions determines NK cell activation or tolerance. Imaging experiments over decades have shown micron and sub-micron scale spatial clustering of activating and inhibitory NKRs. The mechanistic roles of these clusters in affecting downstream signaling and activation are often unclear. To this end, we developed a predictive in silico framework by combining spatially resolved mechanistic agent based modeling, published TIRF imaging data, and parameter estimation to determine mechanisms by which formation and spatial movements of activating NKG2D microclusters affect early time NKG2D signaling kinetics in a human cell line NKL. We show co-clustering of NKG2D and the guanosine nucleotide exchange factor Vav1 in NKG2D microclusters plays a dominant role over ligand (ULBP3) rebinding in increasing production of phospho-Vav1(pVav1), an activation marker of early NKG2D signaling. The in silico model successfully predicts several scenarios of inhibition of NKG2D signaling and time course of NKG2D spatial clustering over a short (~3 min) interval. Modeling shows the presence of a spatial positive feedback relating formation and centripetal movements of NKG2D microclusters, and pVav1 production offers flexibility towards suppression of activating signals by inhibitory KIR ligands organized in inhomogeneous spatial patterns (e.g., a ring). Our in silico framework marks a major improvement in developing spatiotemporal signaling models with quantitatively estimated model parameters using imaging data.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010114","type":"journal-article","created":{"date-parts":[[2022,5,18]],"date-time":"2022-05-18T13:40:48Z","timestamp":1652881248000},"page":"e1010114","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Spatially resolved in silico modeling of NKG2D signaling kinetics suggests a key role of NKG2D and Vav1 Co-clustering in generating natural killer cell activation"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0497-3742","authenticated-orcid":true,"given":"Rajdeep Kaur","family":"Grewal","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9649-4698","authenticated-orcid":true,"given":"Jayajit","family":"Das","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,5,18]]},"reference":[{"issue":"5","key":"pcbi.1010114.ref001","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/ni1581","article-title":"Up on the tightrope: natural killer cell activation and inhibition","volume":"9","author":"LL Lanier","year":"2008","journal-title":"Nature immunology"},{"key":"pcbi.1010114.ref002","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1146\/annurev-immunol-020711-075005","article-title":"Controlling natural killer cell responses: integration of signals for activation and inhibition","volume":"31","author":"EO Long","year":"2013","journal-title":"Annu Rev 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receptors acting locally","volume":"187","author":"A Kaplan","year":"2011","journal-title":"The Journal of Immunology"},{"key":"pcbi.1010114.ref012","doi-asserted-by":"crossref","first-page":"605","DOI":"10.3389\/fimmu.2019.00605","article-title":"Spatial clustering of receptors and signaling molecules regulates NK cell response to peptide repertoire changes","volume":"10","author":"B Mbiribindi","year":"2019","journal-title":"Frontiers in immunology"},{"issue":"8","key":"pcbi.1010114.ref013","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1002076","article-title":"Boltzmann Energy-based Image Analysis Demonstrates that Extracellular Domain Size Differences Explain Protein Segregation at Immune Synapses","volume":"7","author":"NJ Burroughs","year":"2011","journal-title":"Plos Comput Biol"},{"issue":"9","key":"pcbi.1010114.ref014","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.4049\/jimmunol.178.9.5606","article-title":"Inhibitory receptor signals suppress ligation-induced recruitment of NKG2D to GM1-Rich membrane domains at the human NK cell immune synapse","volume":"178","author":"J Endt","year":"2007","journal-title":"Journal of Immunology"},{"issue":"5","key":"pcbi.1010114.ref015","doi-asserted-by":"crossref","first-page":"e96264","DOI":"10.15252\/embj.201696264","article-title":"Actin retrograde flow controls natural killer cell response by regulating the conformation state of SHP-1","volume":"37","author":"O Matalon","year":"2018","journal-title":"The EMBO journal"},{"issue":"175","key":"pcbi.1010114.ref016","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2001325","article-title":"Integration of activating and inhibitory receptor signaling by regulated phosphorylation of Vav1 in immune cells","volume":"4","author":"S Mesecke","year":"2011","journal-title":"Sci Signal"},{"issue":"6","key":"pcbi.1010114.ref017","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nri1374","article-title":"Mathematical and 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weapons?","volume":"3","author":"F Colucci","year":"2002","journal-title":"Nature immunology"},{"issue":"5","key":"pcbi.1010114.ref021","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/ni1325","article-title":"NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells","volume":"7","author":"JL Upshaw","year":"2006","journal-title":"Nature immunology"},{"issue":"6612","key":"pcbi.1010114.ref022","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/385169a0","article-title":"Phosphotyrosine-dependent activation of Rac-1 GDP\/GTP exchange by the vav proto-oncogene product","volume":"385","author":"P Crespo","year":"1997","journal-title":"Nature"},{"issue":"3","key":"pcbi.1010114.ref023","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1128\/MCB.17.3.1346","article-title":"Lck regulates Vav activation of members of the Rho family of GTPases","volume":"17","author":"J Han","year":"1997","journal-title":"Molecular and cellular biology"},{"issue":"3","key":"pcbi.1010114.ref024","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1084\/jem.20021995","article-title":"Vav1 phosphorylation is induced by \u03b22 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization","volume":"198","author":"B Riteau","year":"2003","journal-title":"The Journal of experimental medicine"},{"issue":"6","key":"pcbi.1010114.ref025","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/j.immuni.2012.03.023","article-title":"The adaptor SAP controls NK cell activation by regulating the enzymes Vav-1 and SHIP-1 and by enhancing conjugates with target cells","volume":"36","author":"Z Dong","year":"2012","journal-title":"Immunity"},{"issue":"3","key":"pcbi.1010114.ref026","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1084\/jem.188.3.549","article-title":"The Vav\u2013Rac1 pathway in cytotoxic lymphocytes regulates the generation of cell-mediated killing","volume":"188","author":"DD Billadeau","year":"1998","journal-title":"The Journal of experimental medicine"},{"issue":"6","key":"pcbi.1010114.ref027","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S1074-7613(00)80276-9","article-title":"Sequential involvement of Lck and SHP-1 with MHC-recognizing receptors on NK cells inhibits FcR-initiated tyrosine kinase activation","volume":"5","author":"BA Binstadt","year":"1996","journal-title":"Immunity"},{"issue":"8","key":"pcbi.1010114.ref028","doi-asserted-by":"crossref","first-page":"4789","DOI":"10.4049\/jimmunol.174.8.4789","article-title":"Functional requirements for signaling through the stimulatory and inhibitory mouse NKR-P1 (CD161) NK cell receptors","volume":"174","author":"B Ljutic","year":"2005","journal-title":"The Journal of Immunology"},{"key":"pcbi.1010114.ref029","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/j.1600-065X.2008.00660.x","article-title":"Negative signaling by inhibitory receptors: the NK cell paradigm","volume":"224","author":"EO Long","year":"2008","journal-title":"Immunological reviews"},{"issue":"1","key":"pcbi.1010114.ref030","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S1074-7613(00)80300-3","article-title":"Recruitment of tyrosine phosphatase HCP by the killer cell inhibitory receptor","volume":"4","author":"DN Burshtyn","year":"1996","journal-title":"Immunity"},{"issue":"17","key":"pcbi.1010114.ref031","doi-asserted-by":"crossref","first-page":"6291","DOI":"10.1128\/MCB.23.17.6291-6299.2003","article-title":"Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity","volume":"23","author":"CC Stebbins","year":"2003","journal-title":"Molecular and cellular biology"},{"issue":"11","key":"pcbi.1010114.ref032","doi-asserted-by":"crossref","first-page":"5042","DOI":"10.1073\/pnas.92.11.5042","article-title":"Kinetic proofreading in T-cell receptor signal transduction","volume":"92","author":"TW McKeithan","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pcbi.1010114.ref033","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1016\/j.bpj.2010.07.061","article-title":"Activation or tolerance of natural killer cells is modulated by ligand quality in a nonmonotonic manner","volume":"99","author":"J. Das","year":"2010","journal-title":"Biophys J"},{"key":"pcbi.1010114.ref034","first-page":"1541","article-title":"Modulation of TCR signaling by tyrosine phosphatases: From autoimmunity to immunotherapy","author":"P Castro-Sanchez","year":"2020","journal-title":"Frontiers in cell and developmental biology"},{"issue":"4","key":"pcbi.1010114.ref035","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.4049\/jimmunol.177.4.2349","article-title":"Vav1 controls DAP10-mediated natural cytotoxicity by regulating actin and microtubule dynamics","volume":"177","author":"DB Graham","year":"2006","journal-title":"The Journal of Immunology"},{"issue":"6","key":"pcbi.1010114.ref036","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S1074-7613(03)00320-0","article-title":"Thermodynamic analysis of degenerate recognition by the NKG2D immunoreceptor: not induced fit but rigid adaptation","volume":"19","author":"BJ McFarland","year":"2003","journal-title":"Immunity"},{"issue":"481","key":"pcbi.1010114.ref037","article-title":"A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D ligand binding","volume":"10","author":"J Zuo","year":"2017","journal-title":"Science signaling"},{"issue":"6","key":"pcbi.1010114.ref038","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1016\/j.bpj.2018.08.018","article-title":"Computational model of chimeric antigen receptors explains site-specific phosphorylation kinetics","volume":"115","author":"JA Rohrs","year":"2018","journal-title":"Biophysical journal"},{"issue":"3","key":"pcbi.1010114.ref039","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1007\/s12195-016-0438-7","article-title":"Predictive model of lymphocyte-specific protein tyrosine kinase (LCK) autoregulation","volume":"9","author":"JA Rohrs","year":"2016","journal-title":"Cellular and molecular bioengineering"},{"issue":"11","key":"pcbi.1010114.ref040","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1046\/j.1432-1033.2003.03604.x","article-title":"Investigation of the kinetics and order of tyrosine phosphorylation in the T-cell receptor \u03b6 chain by the protein tyrosine kinase Lck","volume":"270","author":"HR Housden","year":"2003","journal-title":"European journal of biochemistry"},{"issue":"12","key":"pcbi.1010114.ref041","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1093\/emboj\/20.12.2995","article-title":"Novel recognition mode between Vav and Grb2 SH3 domains","volume":"20","author":"M Nishida","year":"2001","journal-title":"The EMBO journal"},{"issue":"46","key":"pcbi.1010114.ref042","doi-asserted-by":"crossref","first-page":"15257","DOI":"10.1021\/bi051126h","article-title":"Acidic region tyrosines provide access points for allosteric activation of the autoinhibited Vav1 Dbl homology domain","volume":"44","author":"GK Amarasinghe","year":"2005","journal-title":"Biochemistry"},{"issue":"5","key":"pcbi.1010114.ref043","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/intbio\/zyaa008","article-title":"Enhancing network activation in natural killer cells: Predictions from in silico modeling","volume":"12","author":"SZ Makaryan","year":"2020","journal-title":"Integrative Biology"},{"issue":"12","key":"pcbi.1010114.ref044","doi-asserted-by":"crossref","first-page":"6198","DOI":"10.4049\/jimmunol.1300464","article-title":"Allelic variation in KIR2DL3 generates a KIR2DL2-like receptor with increased binding to its HLA-C ligand","volume":"190","author":"WR Frazier","year":"2013","journal-title":"The Journal of Immunology"},{"issue":"40","key":"pcbi.1010114.ref045","doi-asserted-by":"crossref","first-page":"28329","DOI":"10.1074\/jbc.274.40.28329","article-title":"Killer cell immunoglobulin receptors and T cell receptors bind peptide-major histocompatibility complex class I with distinct thermodynamic and kinetic properties","volume":"274","author":"K Maenaka","year":"1999","journal-title":"Journal of Biological Chemistry"},{"issue":"4","key":"pcbi.1010114.ref046","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1046\/j.1365-2567.1999.00825.x","article-title":"H-2Dd engagement of Ly49A leads directly to Ly49A phosphorylation and recruitment of SHP1","volume":"97","author":"M Daws","year":"1999","journal-title":"Immunology"},{"issue":"3","key":"pcbi.1010114.ref047","doi-asserted-by":"crossref","first-page":"e1601692","DOI":"10.1126\/sciadv.1601692","article-title":"Biophysical assay for tethered signaling reactions reveals tether-controlled activity for the phosphatase SHP-1","volume":"3","author":"J Goyette","year":"2017","journal-title":"Science advances"},{"issue":"10","key":"pcbi.1010114.ref048","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1016\/j.bpj.2021.03.019","article-title":"Determination of the molecular reach of the protein tyrosine phosphatase SHP-1","volume":"120","author":"L Clemens","year":"2021","journal-title":"Biophysical Journal"},{"issue":"285","key":"pcbi.1010114.ref049","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2003947","article-title":"Superresolution Microscopy Reveals Nanometer-Scale Reorganization of Inhibitory Natural Killer Cell Receptors upon Activation of NKG2D","volume":"6","author":"SV Pageon","year":"2013","journal-title":"Sci Signal"},{"issue":"10","key":"pcbi.1010114.ref050","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.4049\/jimmunol.177.10.6904","article-title":"Segregation of HLA-C from ICAM-1 at NK cell immune synapses is controlled by its cell surface density","volume":"177","author":"CR Almeida","year":"2006","journal-title":"Journal of Immunology"},{"issue":"24","key":"pcbi.1010114.ref051","doi-asserted-by":"crossref","first-page":"8583","DOI":"10.1128\/MCB.01477-07","article-title":"Phosphatidylinositol 3-kinase activation is required to form the NKG2D immunological synapse","volume":"27","author":"E Giurisato","year":"2007","journal-title":"Mol Cell Biol"},{"issue":"2","key":"pcbi.1010114.ref052","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1080\/00018730110117433","article-title":"Theory of phase-ordering kinetics","volume":"51","author":"AJ Bray","year":"2002","journal-title":"Adv Phys"},{"issue":"6","key":"pcbi.1010114.ref053","doi-asserted-by":"crossref","first-page":"3686","DOI":"10.1529\/biophysj.105.065300","article-title":"Effects of receptor clustering on ligand dissociation kinetics: theory and simulations","volume":"89","author":"M Gopalakrishnan","year":"2005","journal-title":"Biophysical Journal"},{"issue":"10","key":"pcbi.1010114.ref054","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.4049\/jimmunol.177.10.6904","article-title":"Segregation of HLA-C from ICAM-1 at NK cell immune synapses is controlled by its cell surface density","volume":"177","author":"CR Almeida","year":"2006","journal-title":"The Journal of Immunology"},{"issue":"24","key":"pcbi.1010114.ref055","first-page":"2375","volume":"7","author":"Guillaume Toledo EaLS","year":"2021","journal-title":"Molecular-scale spatio-chemical control of the activating-inhibitory signal integration in NK cells Science Advances"},{"issue":"4","key":"pcbi.1010114.ref056","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.immuni.2012.03.007","article-title":"The Adaptor Protein Crk Controls Activation and Inhibition of Natural Killer Cells","volume":"36","author":"DF Liu","year":"2012","journal-title":"Immunity"},{"key":"pcbi.1010114.ref057","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2015.00495","article-title":"NKp46 clusters at the immune synapse and regulates NK cell polarization","volume":"6","author":"U Hadad","year":"2015","journal-title":"Frontiers in immunology"},{"issue":"9","key":"pcbi.1010114.ref058","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1016\/j.celrep.2016.04.075","article-title":"The Size of Activating and Inhibitory Killer Ig-like Receptor Nanoclusters Is Controlled by the Transmembrane Sequence and Affects Signaling","volume":"15","author":"A Oszmiana","year":"2016","journal-title":"Cell Rep"},{"issue":"7","key":"pcbi.1010114.ref059","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1182\/blood-2007-01-070656","article-title":"Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V\/V and V\/F polymorphism","volume":"110","author":"E Hatjiharissi","year":"2007","journal-title":"Blood"},{"issue":"9","key":"pcbi.1010114.ref060","doi-asserted-by":"crossref","first-page":"6210","DOI":"10.1074\/jbc.M609064200","article-title":"Affinity and kinetic analysis of Fc\u03b3 receptor IIIa (CD16a) binding to IgG ligands","volume":"282","author":"P Li","year":"2007","journal-title":"Journal of Biological Chemistry"},{"issue":"8","key":"pcbi.1010114.ref061","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/s41565-020-0719-0","article-title":"Role of nanoscale antigen organization on B-cell activation probed using DNA origami","volume":"15","author":"R Veneziano","year":"2020","journal-title":"Nature nanotechnology"},{"key":"pcbi.1010114.ref062","article-title":"DNA origami patterning of synthetic T cell receptors reveals spatial control of the sensitivity and kinetics of signal activation","author":"R Dong","year":"2021","journal-title":"bioRxiv"},{"issue":"7054","key":"pcbi.1010114.ref063","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1038\/nature03884","article-title":"The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor","volume":"436","author":"S Gasser","year":"2005","journal-title":"Nature"},{"key":"pcbi.1010114.ref064","first-page":"299","article-title":"A wish-list for modeling immunological synapses","author":"ML Dustin","year":"2018","journal-title":"Systems Immunology: CRC Press"},{"issue":"3","key":"pcbi.1010114.ref065","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.immuni.2007.01.013","article-title":"The stimulatory potency of T cell antigens is influenced by the formation of the immunological synapse","volume":"26","author":"S Cemerski","year":"2007","journal-title":"Immunity"},{"issue":"6","key":"pcbi.1010114.ref066","doi-asserted-by":"crossref","first-page":"3665","DOI":"10.1529\/biophysj.104.045609","article-title":"Pattern formation during T-cell adhesion","volume":"87","author":"TR Weikl","year":"2004","journal-title":"Biophysical journal"},{"issue":"12","key":"pcbi.1010114.ref067","doi-asserted-by":"crossref","first-page":"6548","DOI":"10.1073\/pnas.111536798","article-title":"Synaptic pattern formation during cellular recognition","volume":"98","author":"S Qi","year":"2001","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"pcbi.1010114.ref068","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/978-1-4939-6881-7_12","article-title":"Mathematical modeling of synaptic patterns","author":"A Siokis","year":"2017","journal-title":"The Immune Synapse: Springer"},{"issue":"3","key":"pcbi.1010114.ref069","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1016\/S0006-3495(04)74211-3","article-title":"Equilibrium thermodynamics of cell-cell adhesion mediated by multiple ligand-receptor pairs","volume":"86","author":"D Coombs","year":"2004","journal-title":"Biophysical journal"},{"issue":"4","key":"pcbi.1010114.ref070","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1016\/S0006-3495(02)73944-1","article-title":"Differential segregation in a cell-cell contact interface: the dynamics of the immunological synapse","volume":"83","author":"NJ Burroughs","year":"2002","journal-title":"Biophysical journal"},{"issue":"12","key":"pcbi.1010114.ref071","doi-asserted-by":"crossref","first-page":"4196","DOI":"10.1529\/biophysj.106.094995","article-title":"Mechanisms of B-cell synapse formation predicted by Monte Carlo simulation","volume":"92","author":"PK Tsourkas","year":"2007","journal-title":"Biophysical journal"},{"issue":"8","key":"pcbi.1010114.ref072","doi-asserted-by":"crossref","first-page":"e1002076","DOI":"10.1371\/journal.pcbi.1002076","article-title":"Boltzmann energy-based image analysis demonstrates that extracellular domain size differences explain protein segregation at immune synapses","volume":"7","author":"NJ Burroughs","year":"2011","journal-title":"Plos Comput Biol"},{"issue":"5","key":"pcbi.1010114.ref073","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.celrep.2018.06.114","article-title":"F-actin-driven CD28-CD80 localization in the immune 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Steblyanko","year":"2015","journal-title":"Journal of Biological Chemistry"},{"issue":"346","key":"pcbi.1010114.ref077","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.2005629","article-title":"A signaling network stimulated by \u03b22 integrin promotes the polarization of lytic granules in cytotoxic cells","volume":"7","author":"M Zhang","year":"2014","journal-title":"Science signaling"},{"issue":"5","key":"pcbi.1010114.ref078","doi-asserted-by":"crossref","first-page":"2918","DOI":"10.4049\/jimmunol.1000761","article-title":"Tethering of intercellular adhesion molecule on target cells is required for LFA-1\u2013dependent NK cell adhesion and granule polarization","volume":"185","author":"CC Gross","year":"2010","journal-title":"The Journal of Immunology"},{"issue":"11","key":"pcbi.1010114.ref079","doi-asserted-by":"crossref","first-page":"6933","DOI":"10.4049\/jimmunol.0803840","article-title":"PI3K links NKG2D signaling to a CrkL pathway involved in natural killer cell 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Crivoi","year":"2013","journal-title":"Langmuir"},{"issue":"4","key":"pcbi.1010114.ref089","doi-asserted-by":"crossref","first-page":"042303","DOI":"10.1103\/PhysRevE.87.042303","article-title":"Amplifying and attenuating the coffee-ring effect in drying sessile nanofluid droplets","volume":"87","author":"A Crivoi","year":"2013","journal-title":"Phys Rev E"},{"issue":"5","key":"pcbi.1010114.ref090","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1091\/mbc.e11-08-0731","article-title":"Actin retrograde flow and actomyosin II arc contraction drive receptor cluster dynamics at the immunological synapse in Jurkat T cells","volume":"23","author":"J Yi","year":"2012","journal-title":"Molecular biology of the cell"},{"issue":"4","key":"pcbi.1010114.ref091","doi-asserted-by":"crossref","first-page":"e00254","DOI":"10.1128\/mSphere.00254-19","article-title":"In silico modeling of biofilm formation by nontypeable Haemophilus influenzae in vivo","volume":"4","author":"JR 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