Comprehensive analysis of αβT-cell receptor repertoires reveals signatures of thymic selection

Abstract

Thymic selection is a multi-stage process that establishes a T-cell immunity that is efficient in fighting foreign pathogens, while not being self-reactive. During the process, T-cell receptor (TCR) alpha; and beta; chains are rearranged to form a highly diverse set of heterodimers that are selected based on their affinity to peptides presented by major histocompatibility molecules (MHC) in the thymus. Here we employ high-throughput TCR sequencing data, theoretical model of TCR rearrangement and dedicated statistical methods to infer how the selection process affects human TCR repertoire on different scales. On a global scale, our results indicate differences in V(D)J gene usage, complementarity determining region 3 (CDR3) amino acid composition, CDR3 physicochemical properties, k-mer composition and differences in loop structure induced by the selection process. On a local scale, we were able to determine enriched TCR motifs and "holes" in repertoire induced by positive and negative selection and characterize their features. Finally, we demonstrated how TCR sequence composition affects lineage commitment via thymic selection and highlighted the effect of individual MHC haplotype. Our results can aid in identification of potentially self-reactive TCRs in donor repertoires in autoimmunity and immunotherapy studies.

Competing Interest Statement

The authors have declared no competing interest.