Abstract
With the increasing ability to use high-throughput next-generation sequencing to quantify the diversity of the human T cell receptor (TCR) repertoire, the ability to use TCR sequences to infer antigen-specificity could greatly aid potential diagnostics and therapeutics. Here, we use a machine-learning approach known as Restricted Boltzmann Machine to develop a sequence-based inference approach to identify antigen-specific TCRs. Our approach combines probabilistic models of TCR sequences with clone abundance information to extract TCR sequence motifs central to an antigen-specific response. We use this model to identify patient personalized TCR motifs that respond to individual tumor and infectious disease antigens, and to accurately discriminate specific from non-specific responses. Furthermore, the hidden structure of the model results in an interpretable representation space where TCRs responding to the same antigen cluster, correctly discriminating the response of TCR to different viral epitopes. The model can be used to identify condition specific responding TCRs. We focus on the examples of TCRs reactive to candidate neoantigens and selected epitopes in experiments of stimulated TCR clone expansion.
Funder
H2020 European Research Council
H2020 Marie Skłodowska-Curie Actions
agence nationale de la recherche
Agence Nationale de la Recherche
National Institutes of Health
Memorial Sloan-Kettering Cancer Center
Mark Foundation For Cancer Research
Stand Up To Cancer
Lustgarten Foundation
Publisher
Public Library of Science (PLoS)
Subject
Computational Theory and Mathematics,Cellular and Molecular Neuroscience,Genetics,Molecular Biology,Ecology,Modelling and Simulation,Ecology, Evolution, Behavior and Systematics
Cited by
11 articles.
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