Statistical modelling of CDR3 sequences provides robust quality control for TCR repertoire datasets

Abstract

T-Cell Receptors (TCRs) show extensive sequence diversity across T cells. This diversity arises from different choices of V and J genes and from insertions and deletions at the V(D)J junction within the Complementary-Determining Region 3 (CDR3) loop. Here, we quantify how V and J gene usage shapes CDR3 length and amino acid composition. In repertoires of TCRs with either unknown or known specificity, we show that CDR3 length is strongly influenced by the number of germline-encoded CDR3 residues in V and J genes, and that, on average, 80% of CDR3 and 65% of CDR3{beta} residues are determined by V and J gene usage. We further show that inconsistencies between V and J gene annotations and CDR3 sequences can be leveraged to identify potential issues in multiple TCR repertoire datasets. Overall, our study quantifies the impact of V and J gene usage on CDR3 length and amino acid composition and provides a robust framework for quality control of TCR repertoire sequencing data.