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

Mikhail V Pogorelyy; Yuval Elhanati; Quentin Marcou; Anastasiia L Sycheva; Ekaterina A Komech; Vadim I Nazarov; Olga V Britanova; Dmitriy M Chudakov; Ilgar Z Mamedov; Yury B Lebedev; Thierry Mora; Aleksandra M Walczak

doi:10.1371/journal.pcbi.1005572

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.

Authors

Affiliations

¹ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation.
² Laboratoire de physique théorique, CNRS, UPMC and École normale supérieure, Paris, France.
³ Pirogov Russian National Research Medical University, Moscow, Russian Federation.
⁴ Masaryk University, Central European Institute of Technology, Brno, Czech Republic.
⁵ Laboratoire de physique statistique, CNRS, UPMC and École normale supérieure, Paris, France.

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

Grants and funding

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.