RESEARCH ARTICLE

Characterization of human αβTCR repertoire and discovery of D-D fusion in TCRβ chains

  • Peipei Liu 1,2 ,
  • Di Liu 3 ,
  • Xi Yang 1,2 ,
  • Jing Gao 1,2 ,
  • Yan Chen 1 ,
  • Xue Xiao 1 ,
  • Fei Liu 1 ,
  • Jing Zou 1 ,
  • Jun Wu 1 ,
  • Juncai Ma 3 ,
  • Fangqing Zhao 5 ,
  • Xuyu Zhou , 1,2 ,
  • George F. Gao , 1,2,4,5 ,
  • Baoli Zhu , 1,2
Expand
  • 1. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China
  • 3. Network Information Center, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
  • 4. Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China
  • 5. Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China

Received date: 01 Mar 2014

Accepted date: 01 Apr 2014

Published date: 27 Aug 2014

Copyright

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The characterization of the human T-cell receptor (TCR) repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we analyzed the diversity and complexity of both the TCRα and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene (TRAV42/DV1). Moreover, we uncovered the presence of tandem TRBD (TRB D gene) usage in ∼2% of the productive human TCRβ CDR3 sequences.

Cite this article

Peipei Liu , Di Liu , Xi Yang , Jing Gao , Yan Chen , Xue Xiao , Fei Liu , Jing Zou , Jun Wu , Juncai Ma , Fangqing Zhao , Xuyu Zhou , George F. Gao , Baoli Zhu . Characterization of human αβTCR repertoire and discovery of D-D fusion in TCRβ chains[J]. Protein & Cell, 2014 , 5(8) : 603 -615 . DOI: 10.1007/s13238-014-0060-1

1
Arstila TP, Casrouge A, Baron V, Even J, Kanellopoulos J, Kourilsky P(1999) A direct estimate of the human alphabeta T cell receptor diversity. Science286: 958-961

DOI

2
Bank I, Book M, Cohen L, Kneller A, Rosental E, Pras M, Bassat IB, Ben-Nun A (1992) Expansion of a unique subpopulation of cytotoxic T cells that express a C alpha V delta 1 T-cell receptor gene in a patient with severe persistent neutropenia. Blood80: 3157-3163

3
Bank I, Cohen L, Kneller A, de Rosbo NK, Book M, Ben-Nun A (2003) Aberrant T-Cell Receptor Signalling of Interferon-γ- and Tumour Necrosis Factor-α-Producing Cytotoxic CD8+Vδ1/Vβ16 T Cells in a Patient with Chronic Neutropenia. Scand J Immunol58: 89-98

DOI

4
Bassing CH, Swat W, Alt FW(2002) The mechanism and regulation of chromosomal V(D)J recombination. Cell109(Suppl): S45-S55

DOI

5
Borgulya P, Kishi H, Uematsu Y, von Boehmer H (1992) Exclusion and inclusion of alpha and beta Tcell receptor alleles. Cell69: 529-537

DOI

6
Castelli C, Mazzocchi A, Salvi S, Anichini A, Sensi M(1992) Use of the V delta 1 variable region in the functional T-cell receptor alpha chain of a WT31+ cytotoxic T lymphocyte clone which speciflcally recognizes HLA-A2 molecule. Scand J Immunol35: 487-494

DOI

7
Freeman JD, Warren RL, Webb JR, Nelson BH, Holt RA(2009) Proflling the T-cell receptor beta-chain repertoire by massively parallel sequencing. Genome Res19: 1817-1824

DOI

8
Fuschiotti P, Pasqual N, Hierle V, Borel E, London J, Marche PN, Jouvin-Marche E (2007) Analysis of the TCR alpha-chain rearrangement proflle in human T lymphocytes. Mol Immunol44: 3380-3388

DOI

9
Genolet R, Stevenson BJ, Farinelli L, Osteras M, Luescher IF(2012) Highly diverse TCRalpha chain repertoire of pre-immune CD8(+) T cells reveals new insights in gene recombination. EMBO J31: 1666-1678

DOI

10
Gorski J, Yassai M, Zhu X, Kissela B, Kissella B, Keever C, Flomenberg N(1994) Circulating T cell repertoire complexity in normal individuals and bone marrow recipients analyzed by CDR3 size spectratyping. Correlation with immune status. J Immunol152: 5109-5119

11
Hempel WM, Stanhope-Baker P, Mathieu N, Huang F, Schlissel MS, Ferrier P(1998) Enhancer control of V(D)Jrecombination at the TCRβ locus: differential effects on DNA cleavage and joining. Genes & Development12: 2305-2317

DOI

12
Huang C, Kanagawa O(2001) Ordered and coordinated rearrangement of the TCR alpha locus: role of secondary rearrangement in thymic selection. J Immunol166: 2597-2601

DOI

13
Klarenbeek PL, Tak PP, van Schaik BD, Zwinderman AH, Jakobs ME, Zhang Z, van Kampen AH, van Lier RA, Baas F, de Vries N (2010) Human T-cell memory consists mainly of unexpanded clones. Immunol Lett133: 42-48

DOI

14
Klarenbeek PL, Remmerswaal EB, ten Berge IJ, Doorenspleet ME, van Schaik BD, Esveldt RE, Koch SD, ten Brinke A, van Kampen AH, Bemelman FJ (2012) Deep sequencing of antiviral T-cell responses to HCMV and EBV in humans reveals a stable repertoire that is maintained for many years. PLoS Pathog8: e1002889

DOI

15
Krangel MS(2009) Mechanics of T cell receptor gene rearrangement. Curr Opin Immunol21: 133-139

DOI

16
Larimore K, McCormick MW, Robins HS, Greenberg PD(2012) Shaping of human germline IgH repertoires revealed by deep sequencing. J Immunol189: 3221-3230

DOI

17
Lefranc MP(2001) Nomenclature of the human T cell receptor genes. Curr Protoc Immunol Appendix 1, Appendix 1O Lefranc MP (2011) From IMGT-ONTOLOGY CLASSIFICATION Axiom to IMGT standardized gene and allele nomenclature: for immunoglobulins (IG) and Tcell receptors (TR). Cold Spring Harb Protoc2011: 627-632

18
Lefranc MP, Rabbitts TH(1990) Genetic organization of the human T-cell receptor gamma and delta loci. Res Immunol141: 565-577

DOI

19
Li H, Ye C, Ji G, Wu X, Xiang Z, Li Y, Cao Y, Liu X, Douek DC, Price DA (2012) Recombinatorial biases and convergent recombination determine interindividual TCRbeta sharing in murine thymocytes. J Immunol189: 2404-2413

DOI

20
Loh EY, Cwirla S, Seraflni AT, Phillips JH, Lanier LL(1988) Human T-cell-receptor delta chain: genomic organization, diversity, and expression in populations of cells. Proc Natl Acad Sci USA85: 9714-9718

DOI

21
Mardis ER(2008) Next-generation DNA sequencing methods. Annu Rev Genomics Hum Genet9: 387-402

DOI

22
Meek KD, Hasemann CA, Capra JD(1989) Novel rearrangements at the immunoglobulin D locus. Inversions and fusions add to IgH somatic diversity. J Exp Med170: 39-57

DOI

23
Miossec C(1990) Further analysis of the T cell receptor gamma/ delta+ peripheral lymphocyte subset. The V delta 1 gene segment is expressed with either C alpha or C delta. J Exp Med171: 1171-1188

DOI

24
Miossec C, Caignard A, Ferradini L, Roman-Roman S, Faure F, Michalaki H, Triebel F, Hercend T(1991) Molecular characterization of human T cell receptor alpha chains including a V delta 1-encoded variable segment. Eur J Immunol21: 1061-1064

DOI

25
Murphy KM, Travers P, Walport M(2007) Janeway’s Immunobiology. UK, Garland Science, London

26
Neller MA, Burrows JM, Rist MJ, Miles JJ, Burrows SR(2013) High frequency of herpesvirus-speciflc clonotypes in the human T cell repertoire can remain stable over decades with minimal turnover. J Virol87: 697-700

DOI

27
Nikolich-Zugich J, Slifka MK, Messaoudi I(2004) The many important facets of T-cell repertoire diversity. Nat Rev Immunol4: 123-132

DOI

28
Olaru A, Petrie HT, Livak F(2005) Beyond the 12/23 rule of VDJ recombination independent of the Rag proteins. J Immunol174: 6220-6226

DOI

29
Ozawa T, Kishi H, Muraguchi A(2006) Ampliflcation and analysis of cDNA generated from a single cell by 5′-RACE: application to isolation of antibody heavy and light chain variable gene sequences from single B cells. Biotechniques40: 469-478

DOI

30
Padovan E, Casorati G, Dellabona P, Meyer S, Brockhaus M, Lanzavecchia A(1993) Expression of two T cell receptor alpha chains: dual receptor T cells. Science262: 422-424

DOI

31
Pannetier C, Cochet M, Darche S, Casrouge A, Zoller M, Kourilsky P(1993) The Sizes of the Cdr3 Hypervariable Regions of the Murine T-Cell Receptor Beta-Chains Vary as a Function of the Recombined Germ-Line Segments. Proc Natl Acad Sci USA90: 4319-4323

DOI

32
Pasqual N, Gallagher M, Aude-Garcia C, Loiodice M, Thuderoz F, Demongeot J, Ceredig R, Marche PN, Jouvin-Marche E (2002) Quantitative and Qualitative Changes in V-J Rearrangements During Mouse Thymocytes Differentiation: Implication For a Limited T Cell Receptor Chain Repertoire. J Exp Med196: 1163-1174

DOI

33
Quigley MF, Greenaway HY, Venturi V, Lindsay R, Quinn KM, Seder RA, Douek DC, Davenport MP, Price DA(2010) Convergent recombination shapes the clonotypic landscape of the naïve T-cell repertoire. Proc Natl Acad Sci U S A107: 19414-19419

DOI

34
Robins HS, Campregher PV, Srivastava SK, Wacher A, Turtle CJ, Kahsai O, Riddell SR, Warren EH, Carlson CS(2009) Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood114: 4099-4107

DOI

35
Robins HS, Srivastava SK, Campregher PV, Turtle CJ, Andriesen J, Riddell SR, Carlson CS, Warren EH(2010) Overlap and effective size of the human CD8+ Tcell receptor repertoire. Sci Transl Med2, 47ra64

36
Roth ME, Holman PO, Kranz DM(1991) Nonrandom use of J alpha gene segments. Influence of V alpha and J alpha gene location. J Immunol147: 1075-1081

37
Ryu CJ, Haines BB, Draganov DD, Kang YH, Whitehurst CE, Schmidt T, Hong HJ, Chen J(2003) The T cell receptor beta enhancer promotes access and pairing of Dbeta and Jbeta gene segments during V(D)J recombination. Proc Natl Acad Sci USA100: 13465-13470

DOI

38
Shendure J, Ji H(2008) Next-generation DNA sequencing. Nat Biotechnol26: 1135-1145

DOI

39
Sherwood AM, Desmarais C, Livingston RJ, Andriesen J, Haussler M, Carlson CS, Robins H(2011). Deep sequencing of the human TCRgamma and TCRbeta repertoires suggests that TCRbeta rearranges after alphabeta and gammadelta T cell commitment. Sci Transl Med3, 90ra61

40
Takihara Y, Tkachuk D, Michalopoulos E, Champagne E, Reimann J, Minden M, Mak TW(1988) Sequence and organization of the diversity, joining, and constant region genes of the human T-cell delta-chain locus. Proc Natl Acad Sci U S A85: 6097-6101

DOI

41
Ueno T, Tomiyama H, Fujiwara M, Oka S, Takiguchi M(2003) HLA class I-restricted recognition of an HIV-derived epitope peptide by a human T cell receptor alpha chain having a Vdelta1 variable segment. Eur J Immunol33: 2910-2916

DOI

42
Venturi V, Quigley MF, Greenaway HY, Ng PC, Ende ZS, McIntosh T, Asher TE, Almeida JR, Levy S, Price DA (2011) A mechanism for TCR sharing between T cell subsets and individuals revealed by pyrosequencing. J Immunol186: 4285-4294

DOI

43
Wang C, Sanders CM, Yang Q, Schroeder HW Jr, Wang E, Babrzadeh F, Gharizadeh B, Myers RM, Hudson JR Jr, Davis RW (2010) High throughput sequencing reveals a complex pattern of dynamic interrelationships among human T cell subsets. Proc Natl Acad Sci U S A107: 1518-1523

DOI

44
Warren RL, Freeman JD, Zeng T, Choe G, Munro S, Moore R, Webb JR, Holt RA(2011) Exhaustive T-cell repertoire sequencing of human peripheral blood samples reveals signatures of antigen selection and a directly measured repertoire size of at least 1 million clonotypes. Genome Res21: 790-797

DOI

45
Yousfl Monod M, Giudicelli V, Chaume D, Lefranc MP(2004) IMGT/ JunctionAnalysis: the flrst tool for the analysis of the immunoglobulin and T cell receptor complex V-J and V-D-J JUNCTIONs. Bioinformatics20(Suppl 1): i379-i385

DOI

Outlines

/