Contact map dependence of a T-cell receptor binding repertoire.

Abstract

The adaptive immune system protects the host from pathogens by discriminating between host and foreign signatures. T cells of the adaptive immune system undergo training to avoid recognition of self-antigenic signatures displayed as peptides bound to the major histocompatibility complex (pMHC) by their T-cell receptors (TCRs). Similarly, T cell responses are directed toward TCRs recognizing non-self pMHC. Reliable prediction of relevant TCR-pMHC recognition is centrally important for understanding adaptive immunity predicting optimized infections and cancer, but currently prohibited by the theoretical diversity of antigens (∼1020) and TCR signatures. We study an affinity-based model for TCR-pMHC binding that uses a crystal structure to inform a distance-based contact map that weights the pairwise amino acid interactions between TCR and pMHC. We find that the TCR-pMHC binding energy distribution depends on the number of contacts and the topology of the contact map of choice; this impacts T-cell negative selection outcome, with higher T-cell recognition probability at higher variances. In addition, we quantify the degree to which neoantigens with mutations in sites with higher contacts are recognized at a higher rate.