Negative T cell selection on non-random peptides promotes robust self-nonself discrimination

Self-foreign discrimination by the immune system was long thought to arise because negative selection in the thymus silences self-reactive T cells. Yet recent data show that this silencing is remarkably incomplete. Here we ask how a repertoire containing many self-reactive cells can nevertheless discriminate self from foreign. We address this question using realistic-scale computational models of the T cell repertoire. Our models show that when foreign peptides dif-fer systematically from self, moderate T cell cross-reactivity skews the post-selection repertoire towards foreign recognition. When no such systematic differences exist, self-foreign discrim-ination is only possible if peptide presentation in the thymus minimizes the co-occurrence of similar, redundant self peptides. These results imply that negative selection needs to be based on non-random self peptides to allow robust self-foreign discrimination for both self-similar and -dissimilar pathogens.