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The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 Jun 1;173(6):1311–1322. doi: 10.1084/jem.173.6.1311

Selection by two powerful antigens may account for the presence of the major population of human peripheral gamma/delta T cells

PMCID: PMC2190840  PMID: 1827824

Abstract

V gamma 9/V delta 2 cells represent a fraction of human gamma/delta cells that is expanded after birth in the periphery, carries markers of activated cells, and becomes a major population in peripheral blood. We found that these cells do not comprise a single population but actually represent two nested sets, the smaller of which, specific for Mycobacterium tuberculosis-pulsed antigen-presenting cells (APC), is contained in a larger set specific for an antigen found on the Molt-4 lymphoma. The larger set, representing 40-80% of all blood gamma/delta cells, is comprised of cells bearing the V gamma 9/C gamma 1 chain. Cells in the smaller, included set have an additional requirement for V delta 2 (and probably for certain permissive junctional regions, since a very small percentage of V gamma 9/V delta 2 cells do not react against mycobacteria-pulsed APC). Optimal stimulation by mycobacteria is dependent on the presence of APC, and is not restricted by classical major histocompatibility complex molecules. Some of the V gamma 9/V delta 2 mycobacteria-specific clones are also stimulated by APC pulsed with different bacteria, such as Listeria monocytogenes and Escherichia coli, indicating that the population includes several different patterns of reactivity. These data establish a relationship in humans between specificity and V gamma/V delta gene usage, and offer an explanation for the peripheral expansion of these gamma/delta cells.

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Selected References

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  1. Abe R., Hodes R. J. T-cell recognition of minor lymphocyte stimulating (Mls) gene products. Annu Rev Immunol. 1989;7:683–708. doi: 10.1146/annurev.iy.07.040189.003343. [DOI] [PubMed] [Google Scholar]
  2. Band H., Hochstenbach F., McLean J., Hata S., Krangel M. S., Brenner M. B. Immunochemical proof that a novel rearranging gene encodes the T cell receptor delta subunit. Science. 1987 Oct 30;238(4827):682–684. doi: 10.1126/science.3672118. [DOI] [PubMed] [Google Scholar]
  3. Bell E. B., Sparshott S. M. Interconversion of CD45R subsets of CD4 T cells in vivo. Nature. 1990 Nov 8;348(6297):163–166. doi: 10.1038/348163a0. [DOI] [PubMed] [Google Scholar]
  4. Bonneville M., Ito K., Krecko E. G., Itohara S., Kappes D., Ishida I., Kanagawa O., Janeway C. A., Murphy D. B., Tonegawa S. Recognition of a self major histocompatibility complex TL region product by gamma delta T-cell receptors. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5928–5932. doi: 10.1073/pnas.86.15.5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Born W., Hall L., Dallas A., Boymel J., Shinnick T., Young D., Brennan P., O'Brien R. Recognition of a peptide antigen by heat shock--reactive gamma delta T lymphocytes. Science. 1990 Jul 6;249(4964):67–69. doi: 10.1126/science.1695022. [DOI] [PubMed] [Google Scholar]
  6. Borst J., van de Griend R. J., van Oostveen J. W., Ang S. L., Melief C. J., Seidman J. G., Bolhuis R. L. A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes. Nature. 1987 Feb 19;325(6106):683–688. doi: 10.1038/325683a0. [DOI] [PubMed] [Google Scholar]
  7. Bottino C., Tambussi G., Ferrini S., Ciccone E., Varese P., Mingari M. C., Moretta L., Moretta A. Two subsets of human T lymphocytes expressing gamma/delta antigen receptor are identifiable by monoclonal antibodies directed to two distinct molecular forms of the receptor. J Exp Med. 1988 Aug 1;168(2):491–505. doi: 10.1084/jem.168.2.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brenner M. B., McLean J., Scheft H., Riberdy J., Ang S. L., Seidman J. G., Devlin P., Krangel M. S. Two forms of the T-cell receptor gamma protein found on peripheral blood cytotoxic T lymphocytes. Nature. 1987 Feb 19;325(6106):689–694. doi: 10.1038/325689a0. [DOI] [PubMed] [Google Scholar]
  9. Bucy R. P., Chen C. L., Cooper M. D. Tissue localization and CD8 accessory molecule expression of T gamma delta cells in humans. J Immunol. 1989 May 1;142(9):3045–3049. [PubMed] [Google Scholar]
  10. 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]
  11. Choi Y. W., Kotzin B., Herron L., Callahan J., Marrack P., Kappler J. Interaction of Staphylococcus aureus toxin "superantigens" with human T cells. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8941–8945. doi: 10.1073/pnas.86.22.8941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. De Libero G., Flesch I., Kaufmann S. H. Mycobacteria-reactive Lyt-2+ T cell lines. Eur J Immunol. 1988 Jan;18(1):59–66. doi: 10.1002/eji.1830180110. [DOI] [PubMed] [Google Scholar]
  14. De Libero G., Kaufmann S. H. Antigen-specific Lyt-2+ cytolytic T lymphocytes from mice infected with the intracellular bacterium Listeria monocytogenes. J Immunol. 1986 Oct 15;137(8):2688–2694. [PubMed] [Google Scholar]
  15. De Libero G., Lanzavecchia A. Establishment of human double-positive thymocyte clones. J Exp Med. 1989 Jul 1;170(1):303–308. doi: 10.1084/jem.170.1.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Falini B., Flenghi L., Pileri S., Pelicci P., Fagioli M., Martelli M. F., Moretta L., Ciccone E. Distribution of T cells bearing different forms of the T cell receptor gamma/delta in normal and pathological human tissues. J Immunol. 1989 Oct 15;143(8):2480–2488. [PubMed] [Google Scholar]
  17. Fisch P., Malkovsky M., Braakman E., Sturm E., Bolhuis R. L., Prieve A., Sosman J. A., Lam V. A., Sondel P. M. Gamma/delta T cell clones and natural killer cell clones mediate distinct patterns of non-major histocompatibility complex-restricted cytolysis. J Exp Med. 1990 May 1;171(5):1567–1579. doi: 10.1084/jem.171.5.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Happ M. P., Kubo R. T., Palmer E., Born W. K., O'Brien R. L. Limited receptor repertoire in a mycobacteria-reactive subset of gamma delta T lymphocytes. Nature. 1989 Dec 7;342(6250):696–698. doi: 10.1038/342696a0. [DOI] [PubMed] [Google Scholar]
  20. Haregewoin A., Soman G., Hom R. C., Finberg R. W. Human gamma delta+ T cells respond to mycobacterial heat-shock protein. Nature. 1989 Jul 27;340(6231):309–312. doi: 10.1038/340309a0. [DOI] [PubMed] [Google Scholar]
  21. Holoshitz J., Koning F., Coligan J. E., De Bruyn J., Strober S. Isolation of CD4- CD8- mycobacteria-reactive T lymphocyte clones from rheumatoid arthritis synovial fluid. Nature. 1989 May 18;339(6221):226–229. doi: 10.1038/339226a0. [DOI] [PubMed] [Google Scholar]
  22. Jalkanen S., Reichert R. A., Gallatin W. M., Bargatze R. F., Weissman I. L., Butcher E. C. Homing receptors and the control of lymphocyte migration. Immunol Rev. 1986 Jun;91:39–60. doi: 10.1111/j.1600-065x.1986.tb01483.x. [DOI] [PubMed] [Google Scholar]
  23. Kabelitz D., Bender A., Schondelmaier S., Schoel B., Kaufmann S. H. A large fraction of human peripheral blood gamma/delta + T cells is activated by Mycobacterium tuberculosis but not by its 65-kD heat shock protein. J Exp Med. 1990 Mar 1;171(3):667–679. doi: 10.1084/jem.171.3.667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kaufmann S. H. Heat shock proteins and the immune response. Immunol Today. 1990 Apr;11(4):129–136. doi: 10.1016/0167-5699(90)90050-j. [DOI] [PubMed] [Google Scholar]
  25. Lanzavecchia A., Scheidegger D. The use of hybrid hybridomas to target human cytotoxic T lymphocytes. Eur J Immunol. 1987 Jan;17(1):105–111. doi: 10.1002/eji.1830170118. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. Mackay C. R., Beya M. F., Matzinger P. Gamma/delta T cells express a unique surface molecule appearing late during thymic development. Eur J Immunol. 1989 Aug;19(8):1477–1483. doi: 10.1002/eji.1830190820. [DOI] [PubMed] [Google Scholar]
  28. Martin L. H., Calabi F., Lefebvre F. A., Bilsland C. A., Milstein C. Structure and expression of the human thymocyte antigens CD1a, CD1b, and CD1c. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9189–9193. doi: 10.1073/pnas.84.24.9189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Matis L. A., Cron R., Bluestone J. A. Major histocompatibility complex-linked specificity of gamma delta receptor-bearing T lymphocytes. Nature. 1987 Nov 19;330(6145):262–264. doi: 10.1038/330262a0. [DOI] [PubMed] [Google Scholar]
  30. McMichael A. J., Pilch J. R., Galfré G., Mason D. Y., Fabre J. W., Milstein C. A human thymocyte antigen defined by a hybrid myeloma monoclonal antibody. Eur J Immunol. 1979 Mar;9(3):205–210. doi: 10.1002/eji.1830090307. [DOI] [PubMed] [Google Scholar]
  31. Modlin R. L., Pirmez C., Hofman F. M., Torigian V., Uyemura K., Rea T. H., Bloom B. R., Brenner M. B. Lymphocytes bearing antigen-specific gamma delta T-cell receptors accumulate in human infectious disease lesions. Nature. 1989 Jun 15;339(6225):544–548. doi: 10.1038/339544a0. [DOI] [PubMed] [Google Scholar]
  32. O'Brien R. L., Happ M. P., Dallas A., Palmer E., Kubo R., Born W. K. Stimulation of a major subset of lymphocytes expressing T cell receptor gamma delta by an antigen derived from Mycobacterium tuberculosis. Cell. 1989 May 19;57(4):667–674. doi: 10.1016/0092-8674(89)90135-9. [DOI] [PubMed] [Google Scholar]
  33. Parker C. M., Groh V., Band H., Porcelli S. A., Morita C., Fabbi M., Glass D., Strominger J. L., Brenner M. B. Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire. J Exp Med. 1990 May 1;171(5):1597–1612. doi: 10.1084/jem.171.5.1597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Porcelli S., Brenner M. B., Greenstein J. L., Balk S. P., Terhorst C., Bleicher P. A. Recognition of cluster of differentiation 1 antigens by human CD4-CD8-cytolytic T lymphocytes. Nature. 1989 Oct 5;341(6241):447–450. doi: 10.1038/341447a0. [DOI] [PubMed] [Google Scholar]
  35. Rust C. J., Verreck F., Vietor H., Koning F. Specific recognition of staphylococcal enterotoxin A by human T cells bearing receptors with the V gamma 9 region. Nature. 1990 Aug 9;346(6284):572–574. doi: 10.1038/346572a0. [DOI] [PubMed] [Google Scholar]
  36. Sharma S., King L. B., Corley R. B. Molecular events during B lymphocyte differentiation. Induction of endogenous mouse mammary tumor proviral envelope transcripts after B cell stimulation. J Immunol. 1988 Oct 1;141(7):2510–2518. [PubMed] [Google Scholar]
  37. Sorger S. B., Hedrick S. M., Fink P. J., Bookman M. A., Matis L. A. Generation of diversity in T cell receptor repertoire specific for pigeon cytochrome c. J Exp Med. 1987 Feb 1;165(2):279–301. doi: 10.1084/jem.165.2.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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]
  39. Spits H., Paliard X., De Vries J. E. Antigen-specific, but not natural killer, activity of T cell receptor-gamma delta cytotoxic T lymphocyte clones involves secretion of N alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester serine esterase and influx of Ca2+ ions. J Immunol. 1989 Sep 1;143(5):1506–1511. [PubMed] [Google Scholar]
  40. 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]
  41. Triebel F., Faure F., Graziani M., Jitsukawa S., Lefranc M. P., Hercend T. A unique V-J-C-rearranged gene encodes a gamma protein expressed on the majority of CD3+ T cell receptor-alpha/beta- circulating lymphocytes. J Exp Med. 1988 Feb 1;167(2):694–699. doi: 10.1084/jem.167.2.694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Triebel F., Faure F., Mami-Chouaib F., Jitsukawa S., Griscelli A., Genevée C., Roman-Roman S., Hercend T. A novel human V delta gene expressed predominantly in the Ti gamma A fraction of gamma/delta+ peripheral lymphocytes. Eur J Immunol. 1988 Dec;18(12):2021–2027. doi: 10.1002/eji.1830181223. [DOI] [PubMed] [Google Scholar]
  43. Vidović D., Roglić M., McKune K., Guerder S., MacKay C., Dembić Z. Qa-1 restricted recognition of foreign antigen by a gamma delta T-cell hybridoma. Nature. 1989 Aug 24;340(6235):646–650. doi: 10.1038/340646a0. [DOI] [PubMed] [Google Scholar]
  44. Wu Y. J., Tian W. T., Snider R. M., Rittershaus C., Rogers P., LaManna L., Ip S. H. Signal transduction of gamma/delta T cell antigen receptor with a novel mitogenic anti-delta antibody. J Immunol. 1988 Sep 1;141(5):1476–1479. [PubMed] [Google Scholar]

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