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.

Laboratoire de physique statistique CNRS UPMC and École normale supérieure Paris France

Laboratoire de physique théorique CNRS UPMC and École normale supérieure Paris France

Masaryk University Central European Institute of Technology Brno Czech Republic

Pirogov Russian National Research Medical University Moscow Russian Federation

Shemyakin Ovchinnikov Institute of Bioorganic Chemistry Moscow Russian Federation

Zobrazit více v PubMed

Venturi V, Kedzierska K, Price DA, Doherty PC, Douek DC, Turner SJ, et al. Sharing of T cell receptors in antigen-specific responses is driven by convergent recombination. Proc Natl Acad Sci. 2006;103(49):18691–6. 10.1073/pnas.0608907103 PubMed DOI PMC

Madi A, Shifrut E, Reich-Zeliger S, Gal H, Best K, Ndifon W, et al. T-cell receptor repertoires share a restricted set of public and abundant CDR3 sequences that are associated with self-related immunity. Genome Res. 2014;24(10):1603–12. 10.1101/gr.170753.113 PubMed DOI PMC

Miles JJ, Douek DC, Price DA. Bias in the αβ T-cell repertoire: implications for disease pathogenesis and vaccination. Immunol Cell Biol. 2011;89(3):375–387. 10.1038/icb.2010.139 PubMed DOI

Neller MA, Ladell K, McLaren JE, Matthews KK, Gostick E, Pentier JM, et al. Naive CD8+ T-cell precursors display structured TCR repertoires and composite antigen-driven selection dynamics. Immunol Cell Biol. 2015;93(October 2014):1–9. 10.1038/icb.2015.17 PubMed DOI PMC

Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, et al. Naive CD4+ T Cell Frequency Varies for Different Epitopes and Predicts Repertoire Diversity and Response Magnitude. Immunity. 2007;27(2):203–213. 10.1016/j.immuni.2007.07.007 PubMed DOI PMC

Venturi V, Quigley MF, Greenaway HY, Ng PC, Ende ZS, McIntosh T, et al. A mechanism for TCR sharing between T cell subsets and individuals revealed by pyrosequencing. J Immunol. 2011;186(7):4285–4294. 10.4049/jimmunol.1003898 PubMed DOI

Elhanati Y, Murugan A, Callan CG, Mora T, Walczak AM. Quantifying selection in immune receptor repertoires. Proc Natl Acad Sci. 2014;111(27):9875–9880. 10.1073/pnas.1409572111 PubMed DOI PMC

Zvyagin IV, Pogorelyy MV, Ivanova ME, Komech EA, Shugay M, Bolotin DA, et al. Distinctive properties of identical twins’ TCR repertoires revealed by high-throughput sequencing. Proc Natl Acad Sci U S A. 2014;111(16):5980–5. 10.1073/pnas.1319389111 PubMed DOI PMC

Venturi V, Rudd BD, Davenport MP. Specificity, promiscuity, and precursor frequency in immunoreceptors. Curr Opin Immunol. 2013;25(5):639–645. 10.1016/j.coi.2013.07.001 PubMed DOI

Robins HS, Srivastava SK, Campregher PV, Turtle CJ, Andriesen J, Riddell SR, et al. Overlap and Effective Size of the Human CD8+ T Cell Receptor Repertoire. Sci Transl Med. 2010;2(47):47ra64–47ra64. 10.1126/scitranslmed.3001442 PubMed DOI PMC

Murugan A, Mora T, Walczak AM, Callan CG. Statistical inference of the generation probability of T-cell receptors from sequence repertoires. Proc Natl Acad Sci. 2012;109(40):16161–16166. 10.1073/pnas.1212755109 PubMed DOI PMC

Shugay M, Bolotin DA, Putintseva EV, Pogorelyy MV, Mamedov IZ, Chudakov DM. Huge overlap of individual TCR beta repertoires. Frontiers in Immunology. 2013;4(466). PubMed PMC

Elhanati Y, Marcou Q, Mora T, Walczak AM. repgenHMM: a dynamic programming tool to infer the rules of immune receptor generation from sequence data. Bioinformatics. 2016;32(13):1943–1951. 10.1093/bioinformatics/btw112 PubMed DOI PMC

Marcou, Q, Mora, T, Walczak, AM. IGoR: a tool for probabilistic high-throughput immune repertoire analysis. In preparation. 2017;. PubMed PMC

Glanville J, Kuo TC, Büdingen HV, Guey L, Berka J, Sundar PD. Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation. Proc Natl Acad Sci. 2011;108(50):20066–20071. 10.1073/pnas.1107498108 PubMed DOI PMC

Wang C, Liu Y, Cavanagh MM, Le Saux S, Qi Q, Roskin KM, et al. B-cell repertoire responses to varicella-zoster vaccination in human identical twins. Proc Natl Acad Sci. 2014;112(2):500–505. 10.1073/pnas.1415875112 PubMed DOI PMC

Hawes GE, Struyk L, ven den Elsen PJ. Differential usage of T cell receptor V gene segments in CD4+ and CD8+ subsets of T lymphocytes in monozygotic twins1. Journal of Immunology. 1993;150:2033–2045. PubMed

Rubelt F, Bolen CR, McGuire HM, Heiden JAV, Gadala-Maria D, Levin M, et al. Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells. Nature communications. 2016;7:11112 10.1038/ncomms11112 PubMed DOI PMC

Qi Q, Cavanagh MM, Le Saux S, NamKoong H, Kim C, Turgano E, et al. Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination. Science Translational Medicine. 2016;8(332):332ra46–332ra46. 10.1126/scitranslmed.aaf1725 PubMed DOI PMC

Benedict CL, Gilfillan S, Thai TH, Kearney JF. Terminal deoxynucleotidyl transferase and repertoire development. Immunol Rev. 2000;175(4):150–157. 10.1111/j.1600-065X.2000.imr017518.x PubMed DOI

George JF, Schroeder HW. Developmental regulation of D beta reading frame and junctional diversity in T cell receptor-beta transcripts from human thymus. Journal of immunology (Baltimore, Md: 1950). 1992;148(4):1230–9. PubMed

Rechavi E, Lev A, Lee YN, Simon AJ, Yinon Y, Lipitz S, et al. Timely and spatially regulated maturation of B and T cell repertoire during human fetal development. Science translational medicine. 2015;7(276):276ra25 10.1126/scitranslmed.aaa0072 PubMed DOI

Britanova OV, Putintseva EV, Shugay M, Merzlyak EM, Turchaninova MA, Staroverov DB, et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol. 2014;192(6):2689–98. 10.4049/jimmunol.1302064 PubMed DOI

Britanova OV, Shugay M, Merzlyak EM, Staroverov DB, Putintseva EV, Turchaninova MA, et al. Dynamics of Individual T Cell Repertoires: From Cord Blood to Centenarians. J Immunol. 2016;196(12):5005–5013. 10.4049/jimmunol.1600005 PubMed DOI

Kivioja T, Vähärautio A, Karlsson K, Bonke M. Counting absolute numbers of molecules using unique molecular identifiers. Nature methods. 2011;9(1):1–5. 10.1038/nmeth.1778 PubMed DOI

Bolotin DA, Mamedov IZ, Britanova OV, Zvyagin IV, Shagin D, Ustyugova SV, et al. Next generation sequencing for TCR repertoire profiling: Platform-specific features and correction algorithms. European Journal of Immunology. 2012;42(11):3073–3083. 10.1002/eji.201242517 PubMed DOI

Schirmer M, D’Amore R, Ijaz UZ, Hall N, Quince C. Illumina error profiles: resolving fine-scale variation in metagenomic sequencing data. BMC Bioinformatics. 2016;17(1):125 10.1186/s12859-016-0976-y PubMed DOI PMC

Teuffel O, Betts DR, Dettling M, Schaub R, Schäfer BW, Niggli FK. Prenatal origin of separate evolution of leukemia in identical twins. Leukemia. 2004;18(10):1624–1629. 10.1038/sj.leu.2403462 PubMed DOI

Ford AM, Ridge Sa, Cabrera ME, Mahmoud H, Steel CM, Chan LC, et al. In utero rearrangements in the trithorax-related oncogene in infant leukaemias. Nature. 1993;363(6427):358–360. 10.1038/363358a0 PubMed DOI

Wiemels JL, Cazzaniga G, Daniotti M, Eden OB, Addison GM, Masera G, et al. Prenatal origin of acute lymphoblastic leukemia in children. Lancet. 1999;354:1499–1503. 10.1016/S0140-6736(99)09403-9 PubMed DOI

Biran V, Bornes M, Aboura A, Masmoudi S, Drunat S, Baumann C, et al. A long-term competent chimeric immune system in a dizygotic dichorionic twin. Pediatrics. 2011;128:e458–e463. 10.1542/peds.2010-3557 PubMed DOI

Lopriore E, Slaghekke F, Middeldorp JM, Klumper FJ, van Lith JM, Walther FJ, et al. Accurate and simple evaluation of vascular anastomoses in monochorionic placenta using colored dye. Journal of visualized experiments: JoVE. 2011;(55):e3208. PubMed PMC

Lewi L, Deprest J, Hecher K. The vascular anastomoses in monochorionic twin pregnancies and their clinical consequences. American Journal of Obstetrics and Gynecology. 2013;208(1):19–30. 10.1016/j.ajog.2012.09.025 PubMed DOI

Turchaninova MA, Britanova OV, Bolotin DA, Shugay M, Putintseva EV, Staroverov DB, et al. Pairing of T-cell receptor chains via emulsion PCR. Eur J Immunol. 2013;43(9):2507–2515. 10.1002/eji.201343453 PubMed DOI

Howie B, Sherwood AM, Berkebile AD, Berka J, Emerson RO, Williamson DW, et al. High-throughput pairing of T cell receptor a and b sequences. Sci Transl Med. 2015;7(301):301ra131 10.1126/scitranslmed.aac5624 PubMed DOI

Quigley MF, Greenaway HY, Venturi V, Lindsay R, Quinn KM, Seder Ra, et al. Convergent recombination shapes the clonotypic landscape of the naive T-cell repertoire. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(45):19414–9. 10.1073/pnas.1010586107 PubMed DOI PMC

Mold JE, Venkatasubrahmanyam S, Burt TD, Michaëlsson J, Rivera JM, Galkina Sa, et al. Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science. 2010;330(6011):1695–1699. 10.1126/science.1196509 PubMed DOI PMC

Schönland SO, Zimmer JK, Lopez-Benitez CM, Widmann T, Ramin KD, Goronzy JJ, et al. Homeostatic control of T-cell generation in neonates. Blood. 2003;102(4):1428–1434. 10.1182/blood-2002-11-3591 PubMed DOI

Naik SH, Perie L, Swart E, Gerlach C, van Rooij N, de Boer RJ, et al. Diverse and heritable lineage imprinting of early haematopoietic progenitors. Nature. 2013;496(7444):229–232. 10.1038/nature12013 PubMed DOI

Shugay M, Britanova OV, Merzlyak EM, Turchaninova MA, Mamedov IZ, Tuganbaev TR, et al. Towards error-free profiling of immune repertoires. Nature methods. 2014;11(6):653–5. 10.1038/nmeth.2960 PubMed DOI

Bolotin DA, Poslavsky S, Mitrophanov I, Shugay M, Mamedov IZ, Putintseva EV, et al. MiXCR: software for comprehensive adaptive immunity profiling. Nature methods. 2015;12(5):380–381. 10.1038/nmeth.3364 PubMed DOI

Nazarov VI, Pogorelyy MV, Komech EA, Zvyagin IV, Bolotin DA, Shugay M, et al. tcR: an R package for T cell receptor repertoire advanced data analysis. BMC bioinformatics. 2015;16(1):175 10.1186/s12859-015-0613-1 PubMed DOI PMC

R Core Team. R: A Language and Environment for Statistical Computing; 2014. Available from: http://www.R-project.org/.

Novel bimodal TRBD1-TRBD2 rearrangements with dual or absent D-region contribute to TRB V-(D)-J combinatorial diversity

A novel unconventional T cell population enriched in Crohn's disease

Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T-cell memory formation after mild COVID-19 infection

Identification of Disease-associated Traits and Clonotypes in the T Cell Receptor Repertoire of Monozygotic Twins Affected by Inflammatory Bowel Diseases

Primary and secondary anti-viral response captured by the dynamics and phenotype of individual T cell clones

Precise tracking of vaccine-responding T cell clones reveals convergent and personalized response in identical twins

Exploring the pre-immune landscape of antigen-specific T cells

Method for identification of condition-associated public antigen receptor sequences

Comparative analysis of murine T-cell receptor repertoires