RESUMO
Introduction: Predicting the binding specificity of T Cell Receptors (TCR) to MHC-peptide complexes (pMHCs) is essential for the development of repertoire-based biomarkers. This affinity may be affected by different components of the TCR, the peptide, and the MHC allele. Historically, the main element used in TCR-peptide binding prediction was the Complementarity Determining Region 3 (CDR3) of the beta chain. However, recently the contribution of other components, such as the alpha chain and the other V gene CDRs has been suggested. We use a highly accurate novel deep learning-based TCR-peptide binding predictor to assess the contribution of each component to the binding. Methods: We have previously developed ERGO-I (pEptide tcR matchinG predictiOn), a sequence-based T-cell receptor (TCR)-peptide binding predictor that employs natural language processing (NLP) -based methods. We improved it to create ERGO-II by adding the CDR3 alpha segment, the MHC typing, V and J genes, and T cell type (CD4+ or CD8+) as to the predictor. We then estimate the contribution of each component to the prediction. Results and Discussion: ERGO-II provides for the first time high accuracy prediction of TCR-peptide for previously unseen peptides. For most tested peptides and all measures of binding prediction accuracy, the main contribution was from the beta chain CDR3 sequence, followed by the beta chain V and J and the alpha chain, in that order. The MHC allele was the least contributing component. ERGO-II is accessible as a webserver at http://tcr2.cs.biu.ac.il/ and as a standalone code at https://github.com/IdoSpringer/ERGO-II.
Assuntos
Regiões Determinantes de Complementaridade/genética , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Éxons VDJ , Área Sob a Curva , Teste de Histocompatibilidade , Humanos , Peptídeos/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismoRESUMO
Current sequencing methods allow for detailed samples of T cell receptors (TCR) repertoires. To determine from a repertoire whether its host had been exposed to a target, computational tools that predict TCR-epitope binding are required. Currents tools are based on conserved motifs and are applied to peptides with many known binding TCRs. We employ new Natural Language Processing (NLP) based methods to predict whether any TCR and peptide bind. We combined large-scale TCR-peptide dictionaries with deep learning methods to produce ERGO (pEptide tcR matchinG predictiOn), a highly specific and generic TCR-peptide binding predictor. A set of standard tests are defined for the performance of peptide-TCR binding, including the detection of TCRs binding to a given peptide/antigen, choosing among a set of candidate peptides for a given TCR and determining whether any pair of TCR-peptide bind. ERGO reaches similar results to state of the art methods in these tests even when not trained specifically for each test. The software implementation and data sets are available at https://github.com/louzounlab/ERGO. ERGO is also available through a webserver at: http://tcr.cs.biu.ac.il/.