Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1992 Jun 1;175(6):1493–1499. doi: 10.1084/jem.175.6.1493

Major histocompatibility complex independent clonal T cell anergy by direct interaction of Staphylococcus aureus enterotoxin B with the T cell antigen receptor

PMCID: PMC2119262  PMID: 1588277

Abstract

The Staphylococcal enterotoxin superantigens stimulate vigorous responses in T cells bearing certain T cell antigen receptor (TCR) V beta regions. In addition to activation, these superantigens also impart negative signals to T cells resulting in a profound state of unresponsiveness or anergy. The Staphylococcus aureus enterotoxins (SE) B and C2 bind to a closely related site on major histocompatibility complex (MHC) human leukocyte antigen (HLA)-DR1 molecules. Only SEB, however, interacts with the TCR V beta 3 region of HA1.7, a human HLA- DR1 restricted T cell clone specific for influenza haemagglutinin. In competition experiments, we demonstrated that the induction of anergy in HA1.7 by SEB is unaffected by the presence of SEC2. These results suggest that SEB-induced anergy is MHC independent and involves a direct interaction between the TCR and SEB. To resolve definitively whether SEB binds directly to T cells in the absence of MHC class II molecules, the cDNAs encoding the HA1.7 TCR were transfected into an MHC class II-negative human T cell line. The addition of SEB to these transfectants resulted in the downregulation of cell surface TCR expression, an increase in the concentration of intracellular calcium ions, the production of lymphokines, and reduced responsiveness to a subsequent challenge with SEB. We conclude that SEB interacts directly with the TCR in the absence of cointeraction with MHC class II molecules, and that this interaction may induce anergy in HA1.7.

Full Text

The Full Text of this article is available as a PDF (750.3 KB).

Selected References

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

  1. Alber G., Hammer D. K., Fleischer B. Relationship between enterotoxic- and T lymphocyte-stimulating activity of staphylococcal enterotoxin B. J Immunol. 1990 Jun 15;144(12):4501–4506. [PubMed] [Google Scholar]
  2. Choi Y. W., Herman A., DiGiusto D., Wade T., Marrack P., Kappler J. Residues of the variable region of the T-cell-receptor beta-chain that interact with S. aureus toxin superantigens. Nature. 1990 Aug 2;346(6283):471–473. doi: 10.1038/346471a0. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. 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]
  5. Concannon P., Pickering L. A., Kung P., Hood L. Diversity and structure of human T-cell receptor beta-chain variable region genes. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6598–6602. doi: 10.1073/pnas.83.17.6598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dellabona P., Peccoud J., Benoist C., Mathis D. T-cell recognition of superantigens: inside or outside the groove? Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):375–381. doi: 10.1101/sqb.1989.054.01.046. [DOI] [PubMed] [Google Scholar]
  7. Fleischer B., Schrezenmeier H. T cell stimulation by staphylococcal enterotoxins. Clonally variable response and requirement for major histocompatibility complex class II molecules on accessory or target cells. J Exp Med. 1988 May 1;167(5):1697–1707. doi: 10.1084/jem.167.5.1697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fraser J. D. High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature. 1989 May 18;339(6221):221–223. doi: 10.1038/339221a0. [DOI] [PubMed] [Google Scholar]
  9. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  10. Grossman D., Cook R. G., Sparrow J. T., Mollick J. A., Rich R. R. Dissociation of the stimulatory activities of staphylococcal enterotoxins for T cells and monocytes. J Exp Med. 1990 Dec 1;172(6):1831–1841. doi: 10.1084/jem.172.6.1831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Herrmann T., Romero P., Sartoris S., Paiola F., Accolla R. S., Maryanski J. L., MacDonald H. R. Staphylococcal enterotoxin-dependent lysis of MHC class II negative target cells by cytolytic T lymphocytes. J Immunol. 1991 Apr 15;146(8):2504–2512. [PubMed] [Google Scholar]
  12. Janeway C. A., Chalupny J., Conrad P. J., Buxser S. An external stimulus that mimics Mls locus responses. J Immunogenet. 1988 Feb-Jun;15(1-3):161–168. doi: 10.1111/j.1744-313x.1988.tb00418.x. [DOI] [PubMed] [Google Scholar]
  13. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kappler J., Kotzin B., Herron L., Gelfand E. W., Bigler R. D., Boylston A., Carrel S., Posnett D. N., Choi Y., Marrack P. V beta-specific stimulation of human T cells by staphylococcal toxins. Science. 1989 May 19;244(4906):811–813. doi: 10.1126/science.2524876. [DOI] [PubMed] [Google Scholar]
  15. Kawabe Y., Ochi A. Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J Exp Med. 1990 Oct 1;172(4):1065–1070. doi: 10.1084/jem.172.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kimura N., Toyonaga B., Yoshikai Y., Du R. P., Mak T. W. Sequences and repertoire of the human T cell receptor alpha and beta chain variable region genes in thymocytes. Eur J Immunol. 1987 Mar;17(3):375–383. doi: 10.1002/eji.1830170312. [DOI] [PubMed] [Google Scholar]
  17. Klein M. H., Concannon P., Everett M., Kim L. D., Hunkapiller T., Hood L. Diversity and structure of human T-cell receptor alpha-chain variable region genes. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6884–6888. doi: 10.1073/pnas.84.19.6884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kotb M., Majumdar G., Tomai M., Beachey E. H. Accessory cell-independent stimulation of human T cells by streptococcal M protein superantigen. J Immunol. 1990 Sep 1;145(5):1332–1336. [PubMed] [Google Scholar]
  19. Lamb J. R., Skidmore B. J., Green N., Chiller J. M., Feldmann M. Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin. J Exp Med. 1983 May 1;157(5):1434–1447. doi: 10.1084/jem.157.5.1434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lindsten T., June C. H., Thompson C. B. Transcription of T cell antigen receptor genes is induced by protein kinase C activation. J Immunol. 1988 Sep 1;141(5):1769–1774. [PubMed] [Google Scholar]
  21. 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]
  22. Marrack P., Kappler J. The staphylococcal enterotoxins and their relatives. Science. 1990 May 11;248(4956):705–711. doi: 10.1126/science.2185544. [DOI] [PubMed] [Google Scholar]
  23. Matthes M., Schrezenmeier H., Homfeld J., Fleischer S., Malissen B., Kirchner H., Fleischer B. Clonal analysis of human T cell activation by the Mycoplasma arthritidis mitogen (MAS). Eur J Immunol. 1988 Nov;18(11):1733–1737. doi: 10.1002/eji.1830181112. [DOI] [PubMed] [Google Scholar]
  24. Mollick J. A., Cook R. G., Rich R. R. Class II MHC molecules are specific receptors for staphylococcus enterotoxin A. Science. 1989 May 19;244(4906):817–820. doi: 10.1126/science.2658055. [DOI] [PubMed] [Google Scholar]
  25. Morgenstern J. P., Land H. A series of mammalian expression vectors and characterisation of their expression of a reporter gene in stably and transiently transfected cells. Nucleic Acids Res. 1990 Feb 25;18(4):1068–1068. doi: 10.1093/nar/18.4.1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  27. O'Hehir R. E., Aguilar B. A., Schmidt T. J., Gollnick S. O., Lamb J. R. Functional inactivation of Dermatophagoides spp. (house dust mite) reactive human T-cell clones. Clin Exp Allergy. 1991 Mar;21(2):209–215. doi: 10.1111/j.1365-2222.1991.tb00832.x. [DOI] [PubMed] [Google Scholar]
  28. O'Hehir R. E., Lamb J. R. Induction of specific clonal anergy in human T lymphocytes by Staphylococcus aureus enterotoxins. Proc Natl Acad Sci U S A. 1990 Nov;87(22):8884–8888. doi: 10.1073/pnas.87.22.8884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ohashi P. S., Mak T. W., Van den Elsen P., Yanagi Y., Yoshikai Y., Calman A. F., Terhorst C., Stobo J. D., Weiss A. Reconstitution of an active surface T3/T-cell antigen receptor by DNA transfer. Nature. 1985 Aug 15;316(6029):606–609. doi: 10.1038/316606a0. [DOI] [PubMed] [Google Scholar]
  30. Okayama H., Berg P. High-efficiency cloning of full-length cDNA. Mol Cell Biol. 1982 Feb;2(2):161–170. doi: 10.1128/mcb.2.2.161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pullen A. M., Wade T., Marrack P., Kappler J. W. Identification of the region of T cell receptor beta chain that interacts with the self-superantigen MIs-1a. Cell. 1990 Jun 29;61(7):1365–1374. doi: 10.1016/0092-8674(90)90700-o. [DOI] [PubMed] [Google Scholar]
  32. Qin S. X., Cobbold S., Benjamin R., Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989 Mar 1;169(3):779–794. doi: 10.1084/jem.169.3.779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rabbitts T. H., Lefranc M. P., Stinson M. A., Sims J. E., Schroder J., Steinmetz M., Spurr N. L., Solomon E., Goodfellow P. N. The chromosomal location of T-cell receptor genes and a T cell rearranging gene: possible correlation with specific translocations in human T cell leukaemia. EMBO J. 1985 Jun;4(6):1461–1465. doi: 10.1002/j.1460-2075.1985.tb03803.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rammensee H. G., Kroschewski R., Frangoulis B. Clonal anergy induced in mature V beta 6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells. Nature. 1989 Jun 15;339(6225):541–544. doi: 10.1038/339541a0. [DOI] [PubMed] [Google Scholar]
  35. Rellahan B. L., Jones L. A., Kruisbeek A. M., Fry A. M., Matis L. A. In vivo induction of anergy in peripheral V beta 8+ T cells by staphylococcal enterotoxin B. J Exp Med. 1990 Oct 1;172(4):1091–1100. doi: 10.1084/jem.172.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Scholl P. R., Diez A., Karr R., Sekaly R. P., Trowsdale J., Geha R. S. Effect of isotypes and allelic polymorphism on the binding of staphylococcal exotoxins to MHC class II molecules. J Immunol. 1990 Jan 1;144(1):226–230. [PubMed] [Google Scholar]
  37. Schönrich G., Kalinke U., Momburg F., Malissen M., Schmitt-Verhulst A. M., Malissen B., Hämmerling G. J., Arnold B. Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell. 1991 Apr 19;65(2):293–304. doi: 10.1016/0092-8674(91)90163-s. [DOI] [PubMed] [Google Scholar]
  38. Sims J. E., Tunnacliffe A., Smith W. J., Rabbitts T. H. Complexity of human T-cell antigen receptor beta-chain constant- and variable-region genes. Nature. 1984 Dec 6;312(5994):541–545. doi: 10.1038/312541a0. [DOI] [PubMed] [Google Scholar]
  39. White J., Herman A., Pullen A. M., Kubo R., Kappler J. W., Marrack P. The V beta-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice. Cell. 1989 Jan 13;56(1):27–35. doi: 10.1016/0092-8674(89)90980-x. [DOI] [PubMed] [Google Scholar]
  40. Yagi J., Baron J., Buxser S., Janeway C. A., Jr Bacterial proteins that mediate the association of a defined subset of T cell receptor:CD4 complexes with class II MHC. J Immunol. 1990 Feb 1;144(3):892–901. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES