Probing Natural Killer Cell Education by Ly49 Receptor Expression Analysis and Computational Modelling in Single MHC Class I Mice 英文参考文献.docVIP

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Probing Natural Killer Cell Education by Ly49 Receptor Expression Analysis and Computational Modelling in Single MHC Class I Mice 英文参考文献.doc

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Probing Natural Killer Cell Education by Ly49 Receptor Expression Analysis and Computational Modelling in Single MHC Class I Mice 英文参考文献

ProbingNaturalKillerCellEducationbyLy49Receptor ExpressionAnalysisandComputationalModellingin SingleMHCClassIMice SofiaJohansson1.,MaliSalmon-Divon2.,MariaH.Johansson1,YishaiPickman3,PetterBrodin1 ,Klas Ka¨rre1,RamitMehr1,3*,PetterHo¨glund1* 1Department of Microbiology Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden, 2EMBL, European Bioinformatics Institute, Wellcome Trust Genome Campus,Cambridge,UnitedKingdom,3TheMinaandEverardGoodmanFacultyofLifeSciences,Bar-IlanUniversity,Ramat-Gan,Israel Abstract Murinenaturalkiller(NK)cellsexpressinhibitoryLy49receptorsforMHCclassImolecules,whichallowsfor‘‘missingself’’ recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I moleculesimposean‘‘educatingimpact’’ontheNKcellpool.Asaresult,micewithdifferentMHCclassIexpressiondisplay differentfrequencydistributionsofLy49receptorcombinationsonNKcells.Twomodelshavebeenputforwardtoexplain thisimpact.Thetwo-stepselectionmodelproposesastochasticLy49receptorexpressionfollowedbyselectionforNKcells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentiallyexpressesLy49receptorsuntilaninteractionofsufficientmagnitudewithself-classIMHCisreachedfortheNK celltomature.Withtheaimtoclarifywhichoneofthesemodelsismostlikelytoreflecttheactualbiologicalprocess,we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, whichwereanalyzedinmiceexpressingsingleMHCclassImolecules.Ourresultsfavourthetwo-stepselectionmodelover thesequentialmodel.Furthermore,theMHCclassIenvironmentfavouredmaturationofNKcellsexpressingoneorafew selfreceptors,suggestingapossiblestepofpositiveselectioninNKcelleducation.BasedonthepredictedLy49binding preferencesrevealedbythemodel,wealsopropose,thatLy49receptorsaremorepromiscuousthanpreviouslythoughtin their interactions with MHC class I molecules, which was supported by functio