Pan-Peptide Meta Learning for T-cell receptor–antigen binding recognition

The identification of the mechanisms by which T-cell receptors (TCRs) interact with human antigens provides a crucial opportunity to develop new vaccines, diagnostics and immunotherapies. However, the accurate prediction and recognition of TCR–antigen pairing represents a substantial computational challenge in immunology. Existing tools only learn the binding patterns of antigens from many known TCR binding repertoires and fail to recognize antigens that have never been presented to the immune system or for which only a few TCR binding repertoires are known. However, the binding specificity for neoantigens or exogenous peptides is crucial for immune studies and immunotherapy. Therefore, we developed Pan-Peptide Meta Learning (PanPep), a general and robust framework to recognize TCR–antigen binding, by combining the concepts of meta-learning and the neural Turing machine. The neural Turing machine adds external memory to avoid forgetting previously learned tasks, which is used here to accurately predict TCR binding specificity with any peptide, particularly unseen ones. We applied PanPep to various challenging clinical tasks, including (1) qualitatively measuring the clonal expansion of T cells; (2) efficiently sorting responsive T cells in tumour neoantigen therapy; and (3) accurately identifying immune-responsive TCRs in a large cohort from a COVID-19 study. Our comprehensive tests show that PanPep outperforms existing tools. PanPep also offers interpretability, revealing the nature of peptide and TCR interactions in 3D crystal structures. We believe PanPep can be a useful tool to decipher TCR–antigen interactions and that it has broad clinical applications. Machine learning methods can predict and recognize binding patterns between T-cell receptors and human antigens, but they struggle with antigens for which no or little data exist regarding interactions with the immune system. A new method called PanPep based on meta-learning can learn quickly on new binding prediction tasks and accurately predicts pairing between T-cell receptors and new antigens.