How Nonuniform Contact Profiles of T Cell Receptors Modulate Thymic Selection Outcomes

T cell receptors (TCRs) bind foreign/self peptides presented by APCs, with a strength that may induce T cell activation. TCRs form through stochastic gene rearrangement, and are selected in the thymus prior to T cell maturation by screening against a number of self-peptides. If a TCR binds too strongly to a self-peptide, or not strongly enough to any, the T cell dies; this shapes the post-selection TCR repertoire to recognize diverse foreign peptides yet avoid self-reactivity. Past work mapped thymic selection to an extreme value problem, and analyzed the statistical properties of the post-selection repertoire as a function of selection parameters. Here, motivated by recent experiments showing that amino acids at certain positions of the TCR sequence are important for inducing self-reactive T cells, we develop a method to incorporate information about TCR structure through its nonuniform contact profile into our model of thymic selection. We find that statistical enrichment or depletion of amino acids is now greatly enhanced at positions making larger contacts, and intriguingly, this effect depends nontrivially on how nonuniform contacts are mediated during thymic selection.