Variability in the local and global composition of human T-cell receptor repertoires during thymic development across cell types and individuals

TL;DR

This study investigates the variability of human T-cell receptor repertoires during thymic development, revealing that individual differences persist across maturation stages and that local sequence similarities reflect cell type distinctions.

Contribution

It provides a comprehensive analysis of TCR repertoire variability across individuals and cell types, introducing a local similarity measure that captures cell-specific repertoire features.

Findings

Inter-individual variability persists throughout T cell development.

Local sequence similarity correlates with cell types.

Whole repertoire models predict local similarity networks.

Abstract

The adaptive immune response relies on T cells that combine phenotypic specialization with diversity of T cell receptors (TCRs) to recognize a wide range of pathogens. TCRs are acquired and selected during T cell maturation in the thymus. Characterizing TCR repertoires across individuals and T cell maturation stages is important for better understanding adaptive immune responses and for developing new diagnostics and therapies. Analyzing a dataset of human TCR repertoires from thymocyte subsets, we find that the variability between individuals generated during the TCR V(D)J recombination is maintained through all stages of T cell maturation and differentiation. The inter-individual variability of repertoires of the same cell type is of comparable magnitude to the variability across cell types within the same individual. To zoom in on smaller scales than whole repertoires, we defined a distance measuring the relative overlap of locally similar sequences in repertoires. We find that the whole repertoire models correctly predict local similarity networks, suggesting a lack of forbidden T cell receptor sequences. The local measure correlates well with distances calculated using whole repertoire traits and carries information about cell types.