Publications
bioRxiv : the preprint server for biologyMay 2025 DOI:
10.1101/2025.04.28.651095

A functionally validated TCR-pMHC database for TCR specificity model development

Messemaker, Marius; Kwee, Bjørn P Y; Moravec, Živa; Álvarez-Salmoral, Daniel; Urbanus, Jos; de Paauw, Sam; Geerligs, Jeroen; Voogd, Rhianne; Morris, Ben; Guislain, Aurélie; Mußmann, Maike; Winkler, Yaël; Steinmetz, Maxime; Iras, Matyas; Marcus, Eric; Teuwen, Jonas; Perrakis, Anastassis; Beijersbergen, Roderick L; Scheper, Wouter; Schumacher, Ton N
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Oligo Pools
Abstract
Accurate prediction of TCR specificity forms a holy grail in immunology and large language models and computational structure predictions provide a path to achieve this. Importantly, current TCR-pMHC prediction models have been trained and evaluated using historical data of unknown quality. Here, we develop and utilize a high-throughput synthetic platform for TCR assembly and evaluation to assess a large fraction of VDJdb-deposited TCR-pMHC entries using a standardized readout of TCR function. Strikingly, this analysis demonstrates that claimed TCR reactivity is only confirmed for 50% of evaluated entries. Intriguingly, the use of TCRbridge to analyze AlphaFold3 confidence metrics reveals a substantial performance in distinguishing functionally validating and non-validating TCRs even though AlphaFold3 was not trained on this task, demonstrating the utility of the validated VDJdb (TCRvdb) database that we generated. We provide TCRvdb as a resource to the community to support training and evaluation of improved predictive TCR specificity models.
Product Used
Oligo Pools

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