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

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

Authors

Milighetti, M.; Nagano, Y.; Henderson, J.; Hershberg, U.; Tiffeau-Mayer, A.; Bitbol, A.-F.; Chain, B.

Abstract

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/TCR{beta} pairing within epitope-specific repertoires. Indeed, we show that the sequences of paired TCR and TCR{beta} 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/TCR{beta} pairing.

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