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

The 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 TCR α /TCR β pairing within epitope-specific repertoires. Indeed, we show that the sequences of paired TCR α and TCR β are 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 allows de novo predictions of TCR α /TCR β pairing.