Abstract
BackgroundBinding of peptides to Major Histocompatibility Complex (MHC) molecules is the single most selective step in the recognition of pathogens by the cellular immune system. The human MHC class I system (HLA-I) is extremely polymorphic. The number of registered HLA-I molecules has now surpassed 1500. Characterizing the specificity of each separately would be a major undertaking.Principal FindingsHere, we have drawn on a large database of known peptide-HLA-I interactions to 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 predicted to bind to previously untested HLA-I molecules, cross-validation, and retrospective prediction of known HIV immune epitopes and endogenous presented peptides, all successfully validate this method. We further demonstrate that the method 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.ConclusionsEncompassing 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 promises to provide new basic insights into HLA structure-function relationships. The method is available at http://www.cbs.dtu.dk/services/NetMHCpan.
Highlights
A large set of quantitative peptide-HLA binding data was used as input to train the NetMHCpan method
A prospective validation was performed using NetMHCpan to identify peptides, which would bind to HLA molecules that specificity-wise were unknown to us
The pan-specific prediction approach was capable of extracting HLA sequence information and correctly relating this to peptide binding even in the absence of any data for the specific query HLA molecule
Summary
Binding of peptides to Major Histocompatibility Complex (MHC) molecules is the single most selective step in the recognition of pathogens by the cellular immune system. Prospective experimental validation of peptides predicted to bind to previously untested HLA-I molecules, cross-validation, and retrospective prediction of known HIV immune epitopes and endogenous presented peptides, all successfully validate this method. Encompassing all HLA molecules, this high-throughput computational method lends itself to epitope searches that are genome- and pathogen-wide, and HLA-wide. It offers a truly global analysis of immune responses supporting rational development of vaccines and immunotherapy.
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