Intra- and inter-chain contacts determine TCR specificity: applying protein co-evolution methods to TCRαβ pairing

Abstract

AbstractThe six complementarity determining regions (CDRs) of the T cell receptor (TCR) form multiple contacts with cognate peptide and major histocompatibility complex, thus determining antigen specificity. However, the importance of contacts between the CDRs themselves remains poorly understood. With a systematic study of over 200 unique TCR structures, we identify consistent intra and inter-chain CDR contact zones. We hypothesise that these interactions may restrict TCRα/TCRβpairing within epitope-specific repertoires. Indeed, we show that the sequences of paired TCRαand TCRβare not independent within the repertoires of TCRs specific for most epitopes examined. We show that this sequence restriction can be quantified using a mutual information framework, can be learnt by co-evolution models without using a training set of known pairs and allowsde novopredictions of TCRα/TCRβpairing.