NetMHCpan, a Method for Quantitative Predictions of Peptide Binding to Any HLA-A and -B Locus Protein of Known Sequence 英文参考文献.docVIP

NetMHCpan,aMethodforQuantitativePredictionsof PeptideBindingtoAnyHLA-Aand-BLocusProteinof KnownSequence MortenNielsen1*,ClausLundegaard1,ThomasBlicher1,KasperLamberth2,MikkelHarndahl2,SuneJustesen2,GustavR?der2,BjoernPeters3, AlessandroSette3,OleLund1,S?renBuus2 1Center for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark, Lyngby, Denmark, 2Department of Experimental Immunology,InstituteofMedicalMicrobiologyandImmunology,UniversityofCopenhagen,Copenhagen,Denmark,3LaJollaInstituteforAllergy andImmunology,SanDiego,California,UnitedStatesofAmerica Background.BindingofpeptidestoMajorHistocompatibilityComplex(MHC)moleculesisthesinglemostselectivestepinthe recognitionofpathogensbythecellularimmunesystem.ThehumanMHCclassIsystem(HLA-I)isextremelypolymorphic.The number of registered HLA-I molecules has now surpassed 1500. Characterizing the specificity of each separately would be amajorundertaking.PrincipalFindings.Here,wehavedrawnonalargedatabaseofknownpeptide-HLA-Iinteractionsto develop a bioinformatics method, which takes both peptide and HLA sequence information into account, and generates quantitative predictions of the affinity of any peptide-HLA-I interaction. Prospective experimental validation of peptides predictedtobindtopreviouslyuntestedHLA-Imolecules,cross-validation,andretrospectivepredictionofknownHIVimmune epitopesandendogenouspresentedpeptides,allsuccessfullyvalidatethismethod.Wefurtherdemonstratethatthemethod can be applied to perform a clustering analysis of MHC specificities and suggest using this clustering to select particularly informative novel MHC molecules for future biochemical and functional analysis. Conclusions. Encompassing all HLA molecules, this high-throughput computational method lends itself to epitope searches that are not only genome- and pathogen-wide, but also HLA-wide. Thus, it offers a truly global analysis of immune responses supporting rational development of vaccines and immunotherapy. It also promise