Data-driven Discovery of Biophysical T Cell Receptor Co-specificity Rules

TL;DR

This paper introduces a data-driven framework to uncover biophysical rules governing T cell receptor co-specificity, revealing key amino acid properties and positions influencing immune response specificity, with implications for understanding adaptive immunity.

Contribution

The study presents a novel optimization framework that systematically identifies biophysical rules for TCR co-specificity, generalizing across diverse ligands and highlighting the importance of steric and non-contact amino acid positions.

Findings

Matching steric properties predicts co-specificity better than hydrophobicity.

Rules generalize to dissimilar ligands unseen during training.

Non-contact positions significantly influence TCR specificity.

Abstract

The biophysical interactions between the T cell receptor (TCR) and its ligands determine the specificity of the cellular immune response. However, the immense diversity of receptors and ligands has made it challenging to discover generalizable rules across the distinct binding affinity landscapes created by different ligands. Here, we present an optimization framework for discovering biophysical rules that predict whether TCRs share specificity to a ligand. Applying this framework to TCRs associated with a collection of SARS-CoV-2 peptides we systematically characterize how co-specificity depends on the type and position of amino-acid differences between receptors. We also demonstrate that the inferred rules generalize to ligands highly dissimilar to any seen during training. Our analysis reveals that matching of steric properties between substituted amino acids is more important for receptor co-specificity than the hydrophobic properties that prominently determine evolutionary substitutability. Our analysis also quantifies the substantial importance of positions not in direct contact with the peptide for specificity. These findings highlight the potential for data-driven approaches to uncover the molecular mechanisms underpinning the specificity of adaptive immune responses.