Persisting fetal clonotypes influence the structure and overlap of adult human T cell receptor repertoires

PLoS Comput Biol. 2017 Jul 6;13(7):e1005572. doi: 10.1371/journal.pcbi.1005572. eCollection 2017 Jul.

Abstract

The diversity of T-cell receptors recognizing foreign pathogens is generated through a highly stochastic recombination process, making the independent production of the same sequence rare. Yet unrelated individuals do share receptors, which together constitute a "public" repertoire of abundant clonotypes. The TCR repertoire is initially formed prenatally, when the enzyme inserting random nucleotides is downregulated, producing a limited diversity subset. By statistically analyzing deep sequencing T-cell repertoire data from twins, unrelated individuals of various ages, and cord blood, we show that T-cell clones generated before birth persist and maintain high abundances in adult organisms for decades, slowly decaying with age. Our results suggest that large, low-diversity public clones are created during pre-natal life, and survive over long periods, providing the basis of the public repertoire.

MeSH terms

  • Aging / genetics*
  • Aging / immunology
  • Base Sequence
  • Cells, Cultured
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / immunology
  • Gene Rearrangement, T-Lymphocyte / genetics*
  • Genetic Variation / genetics*
  • Humans
  • Molecular Sequence Data
  • Receptors, Antigen, T-Cell / physiology*
  • Recombination, Genetic
  • T-Cell Antigen Receptor Specificity / genetics*
  • Twins, Monozygotic / genetics*

Substances

  • Receptors, Antigen, T-Cell

Grant support

TRB/TRA libraries sequencing, raw sequencing data processing and reconstruction of TRB/TRA repertoires were supported by Russian Science Foundation (http://rscf.ru/en) grant №15-15-00178. Work was also partially supported by Russian Science Foundation (http://rscf.ru/en) project №14-14-00533 (to DMC, molecular barcoded data analysis), and partially supported by Skoltech Systems Biology Fellowship (http://www.skoltech.ru/en/2016/04/the-winners-of-the-systems-biology-fellowship-program/) to MVP (sequence sharing data analysis). This work was partially supported by European Research Council (https://erc.europa.eu/) Starting Grant n. 306312. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.