Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Aug;96(2):1108–1117. doi: 10.1172/JCI118097

The delta T cell receptor repertoire in human colon and peripheral blood is oligoclonal irrespective of V region usage.

W Holtmeier 1, Y Chowers 1, A Lumeng 1, E Morzycka-Wroblewska 1, M F Kagnoff 1
PMCID: PMC185300  PMID: 7635946

Abstract

The majority of gamma/delta T cell receptors (TCR) in the human intestinal mucosa are thought to use the TCRDV1 (V delta 1) variable region gene segment, whereas gamma/delta T cells in the circulation predominantly express the TCRDV2 (V delta 2) gene segment. delta T cell receptors that use the TCRDV2 variable region gene segment generally have been regarded as highly diverse, whereas those that use the TCRDV1 gene segment are oligoclonal, whether present in the intestinal tract or in peripheral blood. We report herein that oligoclonality is a general feature of the peripheral delta T cell receptor repertoire in healthy human adults, irrespective of the variable region used and regardless of whether gamma/delta T cells reside in the intestinal mucosa or in peripheral blood. In addition, the delta T cell receptor repertoire is shown to be highly compartmentalized between such sites as the colon and peripheral blood, relatively stable over at least a 10-16-mo period, and unique in each individual. Further, the spectrum of variable region genes used by delta T cell receptor transcripts in the human colon is greater than previously recognized. Thus, in addition to the TCRDV1 and TCRDV2 variable region gene segments, delta T cell receptors in normal intestinal mucosa can use TCRDV3 (V delta 3) and TCRAV (V alpha) gene segments which, in some individuals, comprise a significant component of the mucosal delta T cell receptor repertoire. Our studies indicate that the potential of delta T cell receptors for extensive diversity is not reflected in the mature human repertoire. Moreover, these findings suggest a model wherein the delta T cell receptor repertoire in the colon and peripheral blood is shaped by selection and clonal expansion of gamma/delta T cells that ultimately seed throughout the length of the colon mucosa and populate the circulation.

Full text

PDF
1108

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Balk S. P., Ebert E. C., Blumenthal R. L., McDermott F. V., Wucherpfennig K. W., Landau S. B., Blumberg R. S. Oligoclonal expansion and CD1 recognition by human intestinal intraepithelial lymphocytes. Science. 1991 Sep 20;253(5026):1411–1415. doi: 10.1126/science.1716785. [DOI] [PubMed] [Google Scholar]
  2. Beldjord K., Beldjord C., Macintyre E., Even P., Sigaux F. Peripheral selection of V delta 1+ cells with restricted T cell receptor delta gene junctional repertoire in the peripheral blood of healthy donors. J Exp Med. 1993 Jul 1;178(1):121–127. doi: 10.1084/jem.178.1.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blumberg R. S., Yockey C. E., Gross G. G., Ebert E. C., Balk S. P. Human intestinal intraepithelial lymphocytes are derived from a limited number of T cell clones that utilize multiple V beta T cell receptor genes. J Immunol. 1993 Jun 1;150(11):5144–5153. [PubMed] [Google Scholar]
  4. Boismenu R., Havran W. L. Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science. 1994 Nov 18;266(5188):1253–1255. doi: 10.1126/science.7973709. [DOI] [PubMed] [Google Scholar]
  5. Borst J., Wicherink A., Van Dongen J. J., De Vries E., Comans-Bitter W. M., Wassenaar F., Van Den Elsen P. Non-random expression of T cell receptor gamma and delta variable gene segments in functional T lymphocyte clones from human peripheral blood. Eur J Immunol. 1989 Sep;19(9):1559–1568. doi: 10.1002/eji.1830190907. [DOI] [PubMed] [Google Scholar]
  6. Breit T. M., Wolvers-Tettero I. L., van Dongen J. J. Unique selection determinant in polyclonal V delta 2-J delta 1 junctional regions of human peripheral gamma delta T lymphocytes. J Immunol. 1994 Mar 15;152(6):2860–2864. [PubMed] [Google Scholar]
  7. Casorati G., De Libero G., Lanzavecchia A., Migone N. Molecular analysis of human gamma/delta+ clones from thymus and peripheral blood. J Exp Med. 1989 Nov 1;170(5):1521–1535. doi: 10.1084/jem.170.5.1521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chien Y. H., Iwashima M., Kaplan K. B., Elliott J. F., Davis M. M. A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation. 1987 Jun 25-Jul 1Nature. 327(6124):677–682. doi: 10.1038/327677a0. [DOI] [PubMed] [Google Scholar]
  9. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  10. Chowers Y., Holtmeier W., Harwood J., Morzycka-Wroblewska E., Kagnoff M. F. The V delta 1 T cell receptor repertoire in human small intestine and colon. J Exp Med. 1994 Jul 1;180(1):183–190. doi: 10.1084/jem.180.1.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chowers Y., Holtmeier W., Morzycka-Wroblewska E., Kagnoff M. F. Inverse PCR amplification of rare T cell receptor delta messages from mucosal biopsy specimens. J Immunol Methods. 1995 Feb 27;179(2):261–263. doi: 10.1016/0022-1759(94)00302-d. [DOI] [PubMed] [Google Scholar]
  12. Dariavach P., Lefranc M. P. First genomic sequence of the human T-cell receptor delta 2 gene (TRDV2). Nucleic Acids Res. 1989 Jun 26;17(12):4880–4880. doi: 10.1093/nar/17.12.4880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Davis M. M., Bjorkman P. J. T-cell antigen receptor genes and T-cell recognition. Nature. 1988 Aug 4;334(6181):395–402. doi: 10.1038/334395a0. [DOI] [PubMed] [Google Scholar]
  14. Davodeau F., Peyrat M. A., Hallet M. M., Gaschet J., Houde I., Vivien R., Vie H., Bonneville M. Close correlation between Daudi and mycobacterial antigen recognition by human gamma delta T cells and expression of V9JPC1 gamma/V2DJC delta-encoded T cell receptors. J Immunol. 1993 Aug 1;151(3):1214–1223. [PubMed] [Google Scholar]
  15. Davodeau F., Peyrat M. A., Hallet M. M., Houde I., Vie H., Bonneville M. Peripheral selection of antigen receptor junctional features in a major human gamma delta subset. Eur J Immunol. 1993 Apr;23(4):804–808. doi: 10.1002/eji.1830230405. [DOI] [PubMed] [Google Scholar]
  16. Davodeau F., Peyrat M. A., Hallet M. M., Vié H., Bonneville M. Characterization of a new functional TCR J delta segment in humans. Evidence for a marked conservation of J delta sequences between humans, mice, and sheep. J Immunol. 1994 Jul 1;153(1):137–142. [PubMed] [Google Scholar]
  17. De Libero G., Casorati G., Giachino C., Carbonara C., Migone N., Matzinger P., Lanzavecchia A. Selection by two powerful antigens may account for the presence of the major population of human peripheral gamma/delta T cells. J Exp Med. 1991 Jun 1;173(6):1311–1322. doi: 10.1084/jem.173.6.1311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. De Libero G., Rocci M. P., Casorati G., Giachino C., Oderda G., Tavassoli K., Migone N. T cell receptor heterogeneity in gamma delta T cell clones from intestinal biopsies of patients with celiac disease. Eur J Immunol. 1993 Feb;23(2):499–504. doi: 10.1002/eji.1830230230. [DOI] [PubMed] [Google Scholar]
  19. Delfau M. H., Hance A. J., Lecossier D., Vilmer E., Grandchamp B. Restricted diversity of V gamma 9-JP rearrangements in unstimulated human gamma/delta T lymphocytes. Eur J Immunol. 1992 Sep;22(9):2437–2443. doi: 10.1002/eji.1830220937. [DOI] [PubMed] [Google Scholar]
  20. Deusch K., Lüling F., Reich K., Classen M., Wagner H., Pfeffer K. A major fraction of human intraepithelial lymphocytes simultaneously expresses the gamma/delta T cell receptor, the CD8 accessory molecule and preferentially uses the V delta 1 gene segment. Eur J Immunol. 1991 Apr;21(4):1053–1059. doi: 10.1002/eji.1830210429. [DOI] [PubMed] [Google Scholar]
  21. Farstad I. N., Halstensen T. S., Fausa O., Brandtzaeg P. Do human Peyer's patches contribute to the intestinal intraepithelial gamma/delta T-cell population? Scand J Immunol. 1993 Nov;38(5):451–458. doi: 10.1111/j.1365-3083.1993.tb02587.x. [DOI] [PubMed] [Google Scholar]
  22. Flanagan B. F., Wheatcroft N. J., Thornton S. M., Christmas S. E. T cell receptor junctional regions of V gamma 9+/V delta 2+ T cell clones in relation to non-MHC restricted cytotoxic activity. Mol Immunol. 1993 May;30(7):659–667. doi: 10.1016/0161-5890(93)90077-o. [DOI] [PubMed] [Google Scholar]
  23. Forrester J. M., Newman L. S., Wang Y., King T. E., Jr, Kotzin B. L. Clonal expansion of lung V delta 1+ T cells in pulmonary sarcoidosis. J Clin Invest. 1993 Jan;91(1):292–300. doi: 10.1172/JCI116184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Genevée C., Chung V., Diu A., Hercend T., Triebel F. TCR gene segments from at least one third of V alpha subfamilies rearrange at the delta locus. Mol Immunol. 1994 Feb;31(2):109–115. doi: 10.1016/0161-5890(94)90083-3. [DOI] [PubMed] [Google Scholar]
  25. Giachino C., Granziero L., Modena V., Maiocco V., Lomater C., Fantini F., Lanzavecchia A., Migone N. Clonal expansions of V delta 1+ and V delta 2+ cells increase with age and limit the repertoire of human gamma delta T cells. Eur J Immunol. 1994 Aug;24(8):1914–1918. doi: 10.1002/eji.1830240830. [DOI] [PubMed] [Google Scholar]
  26. Groh V., Porcelli S., Fabbi M., Lanier L. L., Picker L. J., Anderson T., Warnke R. A., Bhan A. K., Strominger J. L., Brenner M. B. Human lymphocytes bearing T cell receptor gamma/delta are phenotypically diverse and evenly distributed throughout the lymphoid system. J Exp Med. 1989 Apr 1;169(4):1277–1294. doi: 10.1084/jem.169.4.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Gross G. G., Schwartz V. L., Stevens C., Ebert E. C., Blumberg R. S., Balk S. P. Distribution of dominant T cell receptor beta chains in human intestinal mucosa. J Exp Med. 1994 Oct 1;180(4):1337–1344. doi: 10.1084/jem.180.4.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Guglielmi P., Davi F., d'Auriol L., Bories J. C., Dausset J., Bensussan A. Use of a variable alpha region to create a functional T-cell receptor delta chain. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5634–5638. doi: 10.1073/pnas.85.15.5634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Haas W., Pereira P., Tonegawa S. Gamma/delta cells. Annu Rev Immunol. 1993;11:637–685. doi: 10.1146/annurev.iy.11.040193.003225. [DOI] [PubMed] [Google Scholar]
  30. Hata S., Clabby M., Devlin P., Spits H., De Vries J. E., Krangel M. S. Diversity and organization of human T cell receptor delta variable gene segments. J Exp Med. 1989 Jan 1;169(1):41–57. doi: 10.1084/jem.169.1.41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hedrick S. M., Engel I., McElligott D. L., Fink P. J., Hsu M. L., Hansburg D., Matis L. A. Selection of amino acid sequences in the beta chain of the T cell antigen receptor. Science. 1988 Mar 25;239(4847):1541–1544. doi: 10.1126/science.2832942. [DOI] [PubMed] [Google Scholar]
  32. Hingorani R., Choi I. H., Akolkar P., Gulwani-Akolkar B., Pergolizzi R., Silver J., Gregersen P. K. Clonal predominance of T cell receptors within the CD8+ CD45RO+ subset in normal human subjects. J Immunol. 1993 Nov 15;151(10):5762–5769. [PubMed] [Google Scholar]
  33. Itohara S., Mombaerts P., Lafaille J., Iacomini J., Nelson A., Clarke A. R., Hooper M. L., Farr A., Tonegawa S. T cell receptor delta gene mutant mice: independent generation of alpha beta T cells and programmed rearrangements of gamma delta TCR genes. Cell. 1993 Feb 12;72(3):337–348. doi: 10.1016/0092-8674(93)90112-4. [DOI] [PubMed] [Google Scholar]
  34. Jarry A., Cerf-Bensussan N., Brousse N., Selz F., Guy-Grand D. Subsets of CD3+ (T cell receptor alpha/beta or gamma/delta) and CD3- lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur J Immunol. 1990 May;20(5):1097–1103. doi: 10.1002/eji.1830200523. [DOI] [PubMed] [Google Scholar]
  35. Kalams S. A., Johnson R. P., Trocha A. K., Dynan M. J., Ngo H. S., D'Aquila R. T., Kurnick J. T., Walker B. D. Longitudinal analysis of T cell receptor (TCR) gene usage by human immunodeficiency virus 1 envelope-specific cytotoxic T lymphocyte clones reveals a limited TCR repertoire. J Exp Med. 1994 Apr 1;179(4):1261–1271. doi: 10.1084/jem.179.4.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Krangel M. S., Yssel H., Brocklehurst C., Spits H. A distinct wave of human T cell receptor gamma/delta lymphocytes in the early fetal thymus: evidence for controlled gene rearrangement and cytokine production. J Exp Med. 1990 Sep 1;172(3):847–859. doi: 10.1084/jem.172.3.847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Liou G. I., Matragoon S. A simple method to homogenize multiple tissue samples in small sizes without cross contamination. Biotechniques. 1992 Nov;13(5):719–719. [PubMed] [Google Scholar]
  38. Loh E. Y., Cwirla S., Serafini A. T., Phillips J. H., Lanier L. L. Human T-cell-receptor delta chain: genomic organization, diversity, and expression in populations of cells. Proc Natl Acad Sci U S A. 1988 Dec;85(24):9714–9718. doi: 10.1073/pnas.85.24.9714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Loh E. Y., Elliott J. F., Cwirla S., Lanier L. L., Davis M. M. Polymerase chain reaction with single-sided specificity: analysis of T cell receptor delta chain. Science. 1989 Jan 13;243(4888):217–220. doi: 10.1126/science.2463672. [DOI] [PubMed] [Google Scholar]
  40. Ohmen J. D., Barnes P. F., Uyemura K., Lu S. Z., Grisso C. L., Modlin R. L. The T cell receptors of human gamma delta T cells reactive to Mycobacterium tuberculosis are encoded by specific V genes but diverse V-J junctions. J Immunol. 1991 Nov 15;147(10):3353–3359. [PubMed] [Google Scholar]
  41. Panchamoorthy G., McLean J., Modlin R. L., Morita C. T., Ishikawa S., Brenner M. B., Band H. A predominance of the T cell receptor V gamma 2/V delta 2 subset in human mycobacteria-responsive T cells suggests germline gene encoded recognition. J Immunol. 1991 Nov 15;147(10):3360–3369. [PubMed] [Google Scholar]
  42. Pluschke G., Ricken G., Taube H., Kroninger S., Melchers I., Peter H. H., Eichmann K., Krawinkel U. Biased T cell receptor V alpha region repertoire in the synovial fluid of rheumatoid arthritis patients. Eur J Immunol. 1991 Nov;21(11):2749–2754. doi: 10.1002/eji.1830211115. [DOI] [PubMed] [Google Scholar]
  43. Posnett D. N., Sinha R., Kabak S., Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994 Feb 1;179(2):609–618. doi: 10.1084/jem.179.2.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rellahan B. L., Bluestone J. A., Houlden B. A., Cotterman M. M., Matis L. A. Junctional sequences influence the specificity of gamma/delta T cell receptors. J Exp Med. 1991 Feb 1;173(2):503–506. doi: 10.1084/jem.173.2.503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Robijn R. J., Bloemendal H., Jainandunsing S., Wiegman L. J., VanBerge-Henegouwen G. P., Logtenberg T., Koningsberger J. C. Phenotypic and molecular characterization of human monoclonal TCR gamma/delta T-cell lines from jejunum and colon of healthy individuals. Scand J Immunol. 1993 Sep;38(3):247–253. doi: 10.1111/j.1365-3083.1993.tb01721.x. [DOI] [PubMed] [Google Scholar]
  46. Rock E. P., Sibbald P. R., Davis M. M., Chien Y. H. CDR3 length in antigen-specific immune receptors. J Exp Med. 1994 Jan 1;179(1):323–328. doi: 10.1084/jem.179.1.323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Roman-Roman S., Ferradini L., Azocar J., Genevée C., Hercend T., Triebel F. Studies on the human T cell receptor alpha/beta variable region genes. I. Identification of 7 additional V alpha subfamilies and 14 J alpha gene segments. Eur J Immunol. 1991 Apr;21(4):927–933. doi: 10.1002/eji.1830210411. [DOI] [PubMed] [Google Scholar]
  48. Rust C., Kooy Y., Peña S., Mearin M. L., Kluin P., Koning F. Phenotypical and functional characterization of small intestinal TcR gamma delta + T cells in coeliac disease. Scand J Immunol. 1992 Apr;35(4):459–468. doi: 10.1111/j.1365-3083.1992.tb02881.x. [DOI] [PubMed] [Google Scholar]
  49. Satyanarayana K., Hata S., Devlin P., Roncarolo M. G., De Vries J. E., Spits H., Strominger J. L., Krangel M. S. Genomic organization of the human T-cell antigen-receptor alpha/delta locus. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8166–8170. doi: 10.1073/pnas.85.21.8166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Schild H., Mavaddat N., Litzenberger C., Ehrich E. W., Davis M. M., Bluestone J. A., Matis L., Draper R. K., Chien Y. H. The nature of major histocompatibility complex recognition by gamma delta T cells. Cell. 1994 Jan 14;76(1):29–37. doi: 10.1016/0092-8674(94)90170-8. [DOI] [PubMed] [Google Scholar]
  51. Spencer J., Isaacson P. G., Diss T. C., MacDonald T. T. Expression of disulfide-linked and non-disulfide-linked forms of the T cell receptor gamma/delta heterodimer in human intestinal intraepithelial lymphocytes. Eur J Immunol. 1989 Jul;19(7):1335–1338. doi: 10.1002/eji.1830190728. [DOI] [PubMed] [Google Scholar]
  52. Takihara Y., Reimann J., Michalopoulos E., Ciccone E., Moretta L., Mak T. W. Diversity and structure of human T cell receptor delta chain genes in peripheral blood gamma/delta-bearing T lymphocytes. J Exp Med. 1989 Feb 1;169(2):393–405. doi: 10.1084/jem.169.2.393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Takihara Y., Tkachuk D., Michalopoulos E., Champagne E., Reimann J., Minden M., Mak T. W. 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 A. 1988 Aug;85(16):6097–6101. doi: 10.1073/pnas.85.16.6097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tamura N., Holroyd K. J., Banks T., Kirby M., Okayama H., Crystal R. G. Diversity in junctional sequences associated with the common human V gamma 9 and V delta 2 gene segments in normal blood and lung compared with the limited diversity in a granulomatous disease. J Exp Med. 1990 Jul 1;172(1):169–181. doi: 10.1084/jem.172.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Uematsu Y. A novel and rapid cloning method for the T-cell receptor variable region sequences. Immunogenetics. 1991;34(3):174–178. doi: 10.1007/BF00205820. [DOI] [PubMed] [Google Scholar]
  56. Ullrich R., Schieferdecker H. L., Ziegler K., Riecken E. O., Zeitz M. gamma delta T cells in the human intestine express surface markers of activation and are preferentially located in the epithelium. Cell Immunol. 1990 Jul;128(2):619–627. doi: 10.1016/0008-8749(90)90053-t. [DOI] [PubMed] [Google Scholar]
  57. Uyemura K., Deans R. J., Band H., Ohmen J., Panchamoorthy G., Morita C. T., Rea T. H., Modlin R. L. Evidence for clonal selection of gamma/delta T cells in response to a human pathogen. J Exp Med. 1991 Sep 1;174(3):683–692. doi: 10.1084/jem.174.3.683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Uyemura K., Klotz J., Pirmez C., Ohmen J., Wang X. H., Ho C., Hoffman W. L., Modlin R. L. Microanatomic clonality of gamma delta T cells in human leishmaniasis lesions. J Immunol. 1992 Feb 15;148(4):1205–1211. [PubMed] [Google Scholar]
  59. Van Kerckhove C., Russell G. J., Deusch K., Reich K., Bhan A. K., DerSimonian H., Brenner M. B. Oligoclonality of human intestinal intraepithelial T cells. J Exp Med. 1992 Jan 1;175(1):57–63. doi: 10.1084/jem.175.1.57. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Weintraub B. C., Jackson M. R., Hedrick S. M. Gamma delta T cells can recognize nonclassical MHC in the absence of conventional antigenic peptides. J Immunol. 1994 Oct 1;153(7):3051–3058. [PubMed] [Google Scholar]
  61. Wilson R. K., Lai E., Concannon P., Barth R. K., Hood L. E. Structure, organization and polymorphism of murine and human T-cell receptor alpha and beta chain gene families. Immunol Rev. 1988 Jan;101:149–172. doi: 10.1111/j.1600-065x.1988.tb00736.x. [DOI] [PubMed] [Google Scholar]
  62. Wucherpfennig K. W., Liao Y. J., Prendergast M., Prendergast J., Hafler D. A., Strominger J. L. Human fetal liver gamma/delta T cells predominantly use unusual rearrangements of the T cell receptor delta and gamma loci expressed on both CD4+CD8- and CD4-CD8- gamma/delta T cells. J Exp Med. 1993 Feb 1;177(2):425–432. doi: 10.1084/jem.177.2.425. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES