Contact map dependence of a T cell receptor binding repertoire

TL;DR

This paper investigates how the contact map topology influences TCR-pMHC binding energy distributions and T cell recognition, revealing that contact structure impacts immune recognition and neoantigen detection.

Contribution

It introduces a contact map-based affinity model for TCR-pMHC interactions, linking contact topology to recognition probability and neoantigen detection.

Findings

Binding energy distribution depends on contact number and topology.

Higher variance in binding energies increases T cell survival.

Neoantigens with mutations at highly contacted sites are more recognized.

Abstract

The T cell arm of the adaptive immune system provides the host protection against unknown pathogens by discriminating between host and foreign material. This discriminatory capability is achieved by the creation of a repertoire of cells each carrying a T cell receptor (TCR) specific to non-self antigens displayed as peptides bound to the major histocompatibility complex (pMHC). The understanding of the dynamics of the adaptive immune system at a repertoire level is complex, due to both the nuanced interaction of a TCR-pMHC pair and to the number of different possible TCR-pMHC pairings, making computationally exact solutions currently unfeasible. To gain some insight into this problem, we study an affinity-based model for TCR-pMHC binding in which a crystal structure is used to generate a distance-based contact map that weights the pairwise amino acid interactions. We find that the TCR-pMHC binding energy distribution strongly depends both on the number of contacts and the repeat structure allowed by the topology of the contact map of choice; this in turn influences T cell recognition probability during negative selection, with higher variances leading to higher survival probabilities. In addition, we quantify the degree to which neoantigens with mutations in sites with higher contacts are recognized at a higher rate.