NNAlign_MA; MHC peptidome Deconvolution for Accurate MHC Binding Motif Characterization and Improved T-cell Epitope Predictions

Bruno Alvarez, Birkir Reynisson, Carolina Barra, Søren Buus, Nicola Ternette, Tim Connelley, Massimo Andreatta, Morten Nielsen

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Abstract

The set of peptides presented on a cell's surface by MHC molecules is known as the immunopeptidome. Current mass spectrometry technologies allow for identification of large peptidomes, and studies have proven these data to be a rich source of information for learning the rules of MHC-mediated antigen presentation. Immunopeptidomes are usually poly-specific, containing multiple sequence motifs matching the MHC molecules expressed in the system under investigation. Motif deconvolution -the process of associating each ligand to its presenting MHC molecule(s)- is therefore a critical and challenging step in the analysis of MS-eluted MHC ligand data. Here, we describe NNAlign_MA, a computational method designed to address this challenge and fully benefit from large, poly-specific data sets of MS-eluted ligands. NNAlign_MA simultaneously performs the tasks of i) clustering peptides into individual specificities; ii) automatic annotation of each cluster to an MHC molecule; and iii) training of a prediction model covering all MHCs present in the training set. NNAlign_MA was benchmarked on large and diverse datasets, covering class I and class II data. In all cases, the method was demonstrated to outperform state-of-the-art methods, effectively expanding the coverage of alleles for which accurate predictions can be made, resulting in improved identification of both eluted ligands and T cell epitopes. Given its high flexibility and ease of use, we expect NNAlign_MA to serve as an effective tool to increase our understanding of the rules of MHC antigen presentation and guide the development of novel T cell-based therapeutics.
Original languageEnglish
JournalMolecular and Cellular Proteomics
Volume18
Issue number12
Pages (from-to)2459-2477
ISSN1535-9476
DOIs
Publication statusPublished - 2019

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