Probing T-cell response by sequence-based probabilistic modeling

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. Author summary Large repertoires of immune cells, such as T cells, are increasingly made available by high-throughput sequencing. Exploiting such datasets to infer how T-cell respond to antigens could help design vaccines and adoptive T-cell therapies. We here propose an approach based on probabilistic machine learning to identify and characterize responding T cells. After learning, this approach is able to distinguish clones that specifically respond to different antigen stimulations. The model parameters and the low-dimensional representations of the T-cell sequences identify sequence motifs underlying T-cell recognition at the molecular level. The approach is illustrated on repertoire data describing in vitro stimulation of T cells by cancer-related neoantigens, as well as on data for common infectious diseases.