The Observed T cell receptor Space database enables paired-chain repertoire mining, coherence analysis and language modelling

Abstract

T cell activation is governed through T cell receptors (TCRs), heterodimers of two sequence-variable chains (often an alpha [α] and beta [β] chain) that recognise linear antigen fragments presented on the cell surfaces. Early sequencing technologies limited the study of immune repertoire TCRs to unpaired transcripts, leading to extensive analysis ofβ-chain data alone as its greater sequence diversity suggested it should dominate antigen recognition. Over time, structural data has revealed that bothαandβchains contribute to binding most antigens and highthroughput single-cell handling technologies have been increasingly applied to obtain samples of complete TCR variable region sequences from repertoires. Despite this, there is currently no repository dedicated to the curation of publicly available paired TCR sequence data. We have addressed this gap by creating the Observed T cell receptor Space (OTS) database, a source of consistently processed and annotated, full-length, paired-chain TCR sequencing data from 50 studies and at least 75 individuals. Currently, OTS contains 5.35M redundant (1.63M nonredundant) predominantly human TCR sequences and, based on recent data availability trends, will grow rapidly. We perform an initial analysis of OTS, leading to the identification of pairing biases, public TCRs, and distinct chain coherence patterns relative to antibodies. We also harness the data to build a publicly available paired-chain TCR language model, providing paired embedding representations and a method for residue in-filling that is conditional on the partner chain. OTS will be updated and maintained as a central community resource and is freely downloadable and available as a web application athttps://opig.stats.ox.ac.uk/webapps/ots.