Advertisement

Dynamic Aspects of TCRα Gene Recombination: Qualitative and Quantitative Assessments of the TCRα Chain Repertoire in Man and Mouse

  • Evelyne Jouvin-MarcheEmail author
  • Patrizia Fuschiotti
  • Patrice Noël Marche
Part of the Advances in Experimental Medicine and Biology book series (volume 650)

Abstract

Most T-lymphocytes express a highly specific antigen receptor (TCR) on their cell surface, consisting of a clonotypic αß-heterodimer. Both α- and β chains are products of somatic rearrangements of V, (D) and J gene segments encoded on the respective loci. The qualitative, quantitative and dynamic aspects of the TCRα chain repertoire of humans and mice have been difficult to estimate, mainly due to locus complexity. Analyses of the T-cell repertoire were first performed at the transcriptional level using classical cloning and sequencing strategies and then later at the genomic level using sensitive multiplex PCR assays that allow surveying the global rearrangement of the TCRAD locus. These all converge and support the conclusion that the V-J recombination pattern in both human and mouse thymus is not random but depends on the reciprocal V and J positions within the locus, thereby limiting the combinatorial diversity of the TCRα chain repertoire. The recombination profile is compatible with a sequential opening of the V region with progressive tracking along the two regions in opposite directions starting from the nearest and then moving towards the most distant V and J gene segments. In this chapter, we report new insights into the degree of human and mouse TCRα chain diversity in thymic and peripheral T-lymphocytes. Since the comparison of human and mouse V-J recombination shows a similar pattern of rearrangement, we suggest that spatial and temporal synchronization on the accessibility of V and J gene segments are general features of V-J rearrangements that are conserved throughout evolution.

Keywords

Gene Segment Chain Repertoire Recombination Profile TCRA Locus Thymic Clonal Deletion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Davis MM, Bjorkman PJ. T-cell antigen receptor genes and T-cell recognition. Nature 1988; 334(6181):395–402.CrossRefPubMedGoogle Scholar
  2. 2.
    Davis MM, Boniface JJ, Reich Z et al. Ligand recognition by alpha beta T-cell receptors. Annu Rev Immunol 1998; 16:523–544.CrossRefPubMedGoogle Scholar
  3. 3.
    Cobb RM, Oestreich KJ, Osipovich OA et al. Accessibility control of V(D)J recombination. Adv Immunol 2006; 91:45–109.CrossRefPubMedGoogle Scholar
  4. 4.
    Cabaniols JP, Fazilleau N, Casrouge A et al. Most alpha/beta T-cell receptor diversity is due to terminal deoxynucleotidyl transferase. J Exp Med 2001; 194(9):1385–1390.CrossRefPubMedGoogle Scholar
  5. 5.
    Malissen M, Trucy J, Letourneur F et al. A T-cell clone expresses two T-cell receptor alpha genes but uses one alpha beta heterodimer for allorecognition and self MHC-restricted antigen recognition. Cell 1988; 55(1):49–59.CrossRefPubMedGoogle Scholar
  6. 6.
    Saito T, Sussman JL, Ashwell JD et al. Marked differences in the efficiency of expression of distinct alpha beta T-cell receptor heterodimers. J Immunol 1989; 143(10):3379–3384.PubMedGoogle Scholar
  7. 7.
    Mason D. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today 1998; 19(9):395–404.CrossRefPubMedGoogle Scholar
  8. 8.
    Reiser JB, Darnault C, Gregoire C et al. CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat Immunol 2003; 4(3):241–247.CrossRefPubMedGoogle Scholar
  9. 9.
    Thompson SD, Pelkonen J, Hurwitz JL. First T-cell receptor alpha gene rearrangements during T-cell ontogeny skew to the 5′ region of the J alpha locus. J Immunol 1990; 145(7):2347–2352.PubMedGoogle Scholar
  10. 10.
    Roth ME, Holman PO, Kranz DM. Nonrandom use of J alpha gene segments. Influence of V alpha and J alpha gene location. J Immunol 1991; 147(3):1075–1081.PubMedGoogle Scholar
  11. 11.
    Rytkonen MA, Hurwitz JL, Thompson SD et al. Restricted onset of T-cell receptor alpha gene rearrangement in fetal and neonatal thymocytes. Eur J Immunol 1996; 26(8):1892–1896.CrossRefPubMedGoogle Scholar
  12. 12.
    Jouvin-Marche E, Aude-Garcia C, Candeias S et al. Differential chronology of TCRADV2 gene use by alpha and delta chains of the mouse TCR. Eur J Immunol 1998; 28(3):818–827.CrossRefPubMedGoogle Scholar
  13. 13.
    Huang C, Kanagawa O. Ordered and coordinated rearrangement of the TCR alpha locus: role of secondary rearrangement in thymic selection. J Immunol 2001; 166(4):2597–2601.PubMedGoogle Scholar
  14. 14.
    Pasqual N, Gallagher M, Aude-Garcia C et al. Quantitative and qualitative changes in V-J alpha rearrangements during mouse thymocytes differentiation: implication for a limited T-cell receptor alpha chain repertoire. J Exp Med 2002; 196(9):1163–1173.CrossRefPubMedGoogle Scholar
  15. 15.
    Sant’Angelo DB, Waterbury PG, Cohen BE et al. The imprint of intrathymic self-peptides on the mature T-cell receptor repertoire. Immunity 1997; 7(4):517–524.CrossRefGoogle Scholar
  16. 16.
    van Meerwijk JP, Marguerat S, Lees RK et al. Quantitative impact of thymic clonal deletion on the T-cell repertoire. J Exp Med 1997; 185(3):377–383.CrossRefPubMedGoogle Scholar
  17. 17.
    Correia-Neves M, Waltzinger C, Mathis D et al. The shaping of the T-cell repertoire. Immunity 2001; 14(1):21–32.CrossRefPubMedGoogle Scholar
  18. 18.
    Pannetier C, Even J, Kourilsky P. T-cell repertoire diversity and clonal expansions in normal and clinical samples. Immunol Today 1995; 16(4):176–181.CrossRefPubMedGoogle Scholar
  19. 19.
    Arstila TP, Casrouge A, Baron V et al. A direct estimate of the human alphabeta T-cell receptor diversity. Science 1999; 286(5441):958–961.CrossRefPubMedGoogle Scholar
  20. 20.
    Lefranc MP. IMGT, the international immunogenetics database. Nucleic Acids Res 2001; 29(1):207–209.CrossRefPubMedGoogle Scholar
  21. 21.
    Baum TP, Pasqual N, Thuderoz F et al. IMGT/GeneInfo: enhancing V(D)J recombination database accessibility. Nucleic Acids Res 2004; 32(1):D51–54.CrossRefPubMedGoogle Scholar
  22. 22.
    Baum TP, Hierle V, Pasqual N et al. IMGT/GeneInfo: T-cell receptor gamma TRG and delta TRD genes in database give access to all TR potential V(D)J recombinations. BMC Bioinformatics 2006; 7(1):224.CrossRefPubMedGoogle Scholar
  23. 23.
    Koop BF, Rowen L, Wang K et al. The human T-cell receptor TCRAC/TCRDC (C alpha/C delta) region: organization, sequence and evolution of 97.6 kb of DNA. Genomics 1994; 19(3):478–493.CrossRefPubMedGoogle Scholar
  24. 24.
    Glusman G, Rowen L, Lee I et al. Comparative genomics of the human and mouse T-cell receptor loci. Immunity 2001; 15(3):337–349.CrossRefPubMedGoogle Scholar
  25. 25.
    Fuschiotti P, Pasqual N, Hierle V et al. Analysis of the TCR alpha-chain rearrangement profile in human T-lymphocytes. Mol Immunol 2007; 44(13):3380–3388.CrossRefPubMedGoogle Scholar
  26. 26.
    Aude-Garcia C, Gallagher M, Marche PN et al. Preferential ADV-AJ association during recombination in the mouse T-cell receptor alpha/delta locus. Immunogenetics 2001; 52(3–4):224–230.CrossRefPubMedGoogle Scholar
  27. 27.
    Mostoslavsky R, Alt FW. Receptor revision in T-cells: an open question? Trends Immunol 2004; 25(6):276–279.CrossRefPubMedGoogle Scholar
  28. 28.
    Bandeira A, Faro J. Quantitative constraints on the scope of negative selection: robustness and weaknesses. Trends Immunol 2003; 24(4):172–173.CrossRefPubMedGoogle Scholar
  29. 29.
    Jouvin-Marche E, Hue I, Marche PN et al. Genomic organization of the mouse T-cell receptor Valphafamily. EMBO J 1990; 9:2141–2150.PubMedGoogle Scholar
  30. 30.
    Gahery-Segard H, Jouvin-Marche E, Six A et al. Germline genomic structure of the B10. A mouse Tcra-V2 gene subfamily. Immunogenetics 1996; 44(4):298–305.CrossRefPubMedGoogle Scholar
  31. 31.
    Krangel MS. Gene segment selection in V(D)J recombination: accessibility and beyond. Nat Immunol 2003; 4(7):624–630.CrossRefPubMedGoogle Scholar
  32. 32.
    Mostoslawsky R, Alt FW, Bassing CH. Chromatin dynamics and locus accessibility in the immune system. Nat Immunol 2003; 4(7):603–606.CrossRefGoogle Scholar
  33. 33.
    Sleckman BP, Bassing CH, Bardon CG et al. Accessibility control of variable region gene assembly during T-cell development. Immunol Rev 1998; 165:121–130.CrossRefPubMedGoogle Scholar
  34. 34.
    Villey I, Caillol D, Selz F et al. Defect in rearrangement of the most 5′ TCR-J alpha following targeted deletion of T early alpha (TEA): implications for TCR alpha locus accessibility. Immunity 1996; 5(4):331–342.CrossRefPubMedGoogle Scholar
  35. 35.
    Hawwari A, Bock C, Krangel MS. Regulation of T-cell receptor alpha gene assembly by a complex hierarchy of germline J alpha promoters. Nat Immunol 2005; 6(5):481–489.CrossRefPubMedGoogle Scholar
  36. 36.
    Mauvieux L, Villey I, de Villartay JP. T early alpha (TEA) regulates initial TCRVAJA rearrangements and leads to TCRJA coincidence. Eur J Immunol 2001; 31(7):2080–2086.CrossRefPubMedGoogle Scholar
  37. 37.
    Abarrategui I, Krangel MS. Noncoding transcription controls downstream promoters to regulate T-cell receptor alpha recombination. EMBO J 2007; 26(20):4380–4390.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Evelyne Jouvin-Marche
    • 1
    Email author
  • Patrizia Fuschiotti
    • 2
  • Patrice Noël Marche
    • 1
  1. 1.INSERM, U823 Faculté de Médecine Institut d’Oncologie/Developpement Albert Bonniot et Institut Français du SangUniversité Joseph Fourier-Grenoble IGrenobleFrance
  2. 2.Department of ImmunologyUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations