Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Aug 16;91(17):8175–8179. doi: 10.1073/pnas.91.17.8175

Nonpeptide ligands for human gamma delta T cells.

Y Tanaka 1, S Sano 1, E Nieves 1, G De Libero 1, D Rosa 1, R L Modlin 1, M B Brenner 1, B R Bloom 1, C T Morita 1
PMCID: PMC44568  PMID: 8058775

Abstract

gamma delta T cells respond to a variety of microbial pathogens and transformed cells. Their limited receptor repertoire and activation by mycobacterial antigens resistant to proteases suggest that they may recognize nonpeptide antigens. We have tested a variety of nonpeptide molecules for stimulation of human gamma delta T cells. Synthetic alkyl phosphates, particularly monoethyl phosphate (MEP), selectively activated gamma delta T cells and stimulated their proliferation in vitro. All gamma delta T cells stimulated by MEP expressed V gamma 2/V delta 2 receptors. The purified natural ligand of mycobacteria is chemically similar to, though distinct from, MEP and contains a phosphate residue that is critical for biological activity. Recognition and expansion of a specific T-cell receptor-bearing population to non-peptide ligands is unprecedented among T cells. We suggest that MEP mimics small natural ligands capable of expanding one subset of gamma delta T cells and that this recognition of nonpeptide antigens may play an important role in human immunity to pathogens.

Full text

PDF
8175

Selected References

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

  1. Behr C., Dubois P. Preferential expansion of V gamma 9 V delta 2 T cells following stimulation of peripheral blood lymphocytes with extracts of Plasmodium falciparum. Int Immunol. 1992 Mar;4(3):361–366. doi: 10.1093/intimm/4.3.361. [DOI] [PubMed] [Google Scholar]
  2. Bertotto A., Gerli R., Spinozzi F., Muscat C., Scalise F., Castellucci G., Sposito M., Candio F., Vaccaro R. Lymphocytes bearing the gamma delta T cell receptor in acute Brucella melitensis infection. Eur J Immunol. 1993 May;23(5):1177–1180. doi: 10.1002/eji.1830230531. [DOI] [PubMed] [Google Scholar]
  3. Brenner M. B., Strominger J. L., Krangel M. S. The gamma delta T cell receptor. Adv Immunol. 1988;43:133–192. [PubMed] [Google Scholar]
  4. 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]
  5. Constant P., Davodeau F., Peyrat M. A., Poquet Y., Puzo G., Bonneville M., Fournié J. J. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science. 1994 Apr 8;264(5156):267–270. doi: 10.1126/science.8146660. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Fisch P., Malkovsky M., Kovats S., Sturm E., Braakman E., Klein B. S., Voss S. D., Morrissey L. W., DeMars R., Welch W. J. Recognition by human V gamma 9/V delta 2 T cells of a GroEL homolog on Daudi Burkitt's lymphoma cells. Science. 1990 Nov 30;250(4985):1269–1273. doi: 10.1126/science.1978758. [DOI] [PubMed] [Google Scholar]
  9. Gerli R., Agea E., Muscat C., Bertotto A., Ercolani R., Bistoni O., Bini P., Spinozzi F., Venanzi F. Functional characterization of T cells bearing the gamma/delta T-cell receptor in patients with primary Sjögren's syndrome. Clin Exp Rheumatol. 1993 May-Jun;11(3):295–299. [PubMed] [Google Scholar]
  10. Goodier M., Fey P., Eichmann K., Langhorne J. Human peripheral blood gamma delta T cells respond to antigens of Plasmodium falciparum. Int Immunol. 1992 Jan;4(1):33–41. doi: 10.1093/intimm/4.1.33. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Hara T., Mizuno Y., Takaki K., Takada H., Akeda H., Aoki T., Nagata M., Ueda K., Matsuzaki G., Yoshikai Y. Predominant activation and expansion of V gamma 9-bearing gamma delta T cells in vivo as well as in vitro in Salmonella infection. J Clin Invest. 1992 Jul;90(1):204–210. doi: 10.1172/JCI115837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Häcker G., Kromer S., Heeg K., Ivanyi J., Wagner H., Pfeffer K. Opportunist mycobacteria express ligands that stimulate production of human V gamma 9V delta 2 T lymphocytes. Infect Immun. 1992 Jul;60(7):2753–2757. doi: 10.1128/iai.60.7.2753-2757.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Janeway C. A., Jr Frontiers of the immune system. Nature. 1988 Jun 30;333(6176):804–806. doi: 10.1038/333804a0. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Meek J. L. Inositol bis-, tris-, and tetrakis(phosphate)s: analysis in tissues by HPLC. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4162–4166. doi: 10.1073/pnas.83.12.4162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. 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]
  18. Mombaerts P., Arnoldi J., Russ F., Tonegawa S., Kaufmann S. H. Different roles of alpha beta and gamma delta T cells in immunity against an intracellular bacterial pathogen. Nature. 1993 Sep 2;365(6441):53–56. doi: 10.1038/365053a0. [DOI] [PubMed] [Google Scholar]
  19. Morita C. T., Verma S., Aparicio P., Martinez C., Spits H., Brenner M. B. Functionally distinct subsets of human gamma/delta T cells. Eur J Immunol. 1991 Dec;21(12):2999–3007. doi: 10.1002/eji.1830211215. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Pamer E. G., Wang C. R., Flaherty L., Lindahl K. F., Bevan M. J. H-2M3 presents a Listeria monocytogenes peptide to cytotoxic T lymphocytes. Cell. 1992 Jul 24;70(2):215–223. doi: 10.1016/0092-8674(92)90097-v. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Pfeffer K., Schoel B., Gulle H., Kaufmann S. H., Wagner H. Primary responses of human T cells to mycobacteria: a frequent set of gamma/delta T cells are stimulated by protease-resistant ligands. Eur J Immunol. 1990 May;20(5):1175–1179. doi: 10.1002/eji.1830200534. [DOI] [PubMed] [Google Scholar]
  25. Porcelli S., Brenner M. B., Band H. Biology of the human gamma delta T-cell receptor. Immunol Rev. 1991 Apr;120:137–183. doi: 10.1111/j.1600-065x.1991.tb00591.x. [DOI] [PubMed] [Google Scholar]
  26. Porcelli S., Morita C. T., Brenner M. B. CD1b restricts the response of human CD4-8- T lymphocytes to a microbial antigen. Nature. 1992 Dec 10;360(6404):593–597. doi: 10.1038/360593a0. [DOI] [PubMed] [Google Scholar]
  27. Raulet D. H., Spencer D. M., Hsiang Y. H., Goldman J. P., Bix M., Liao N. S., Zijstra M., Jaenisch R., Correa I. Control of gamma delta T-cell development. Immunol Rev. 1991 Apr;120:185–204. doi: 10.1111/j.1600-065x.1991.tb00592.x. [DOI] [PubMed] [Google Scholar]
  28. Selin L. K., Stewart S., Shen C., Mao H. Q., Wilkins J. A. Reactivity of gamma delta T cells induced by the tumour cell line RPMI 8226: functional heterogeneity of clonal populations and role of GroEL heat shock proteins. Scand J Immunol. 1992 Jul;36(1):107–117. doi: 10.1111/j.1365-3083.1992.tb02946.x. [DOI] [PubMed] [Google Scholar]
  29. Spits H., Paliard X., Vandekerckhove Y., van Vlasselaer P., de Vries J. E. Functional and phenotypic differences between CD4+ and CD4- T cell receptor-gamma delta clones from peripheral blood. J Immunol. 1991 Aug 15;147(4):1180–1188. [PubMed] [Google Scholar]
  30. Sumida T., Maeda T., Takahashi H., Yoshida S., Yonaha F., Sakamoto A., Tomioka H., Koike T., Yoshida S. Predominant expansion of V gamma 9/V delta 2 T cells in a tularemia patient. Infect Immun. 1992 Jun;60(6):2554–2558. doi: 10.1128/iai.60.6.2554-2558.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES