Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Sep 1;184(3):971–980. doi: 10.1084/jem.184.3.971

An Epstein-Barr virus-associated superantigen

PMCID: PMC2192769  PMID: 9064357

Abstract

More than 90% of adults are latently infected with Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, a self-limiting lymphoproliferative disease characterized by extensive T cell activation. Reactivation of this herpesvirus during immunosuppression is often associated with oncogenesis. These considerations led us to analyze the early events that occur after exposure of the immune system to EBV. Strong major histocompatibility complex (MHC) class II- dependent but not MHC-restricted, T cell proliferation was observed in vitro in response to autologous, lytically infected EBV-transformed B cells. By measuring the appearance of the early activation marker CD69 on individual T cell V beta subsets, we could demonstrate selective activation of human V beta 13- T cells. This was confirmed with murine T cell hybridomas expressing various human BV genes. While EBV- Burkitt's lymphoma cells were nonstimulatory, they induced V beta- restricted T cell activation after EBV infection. EBV specific activation was also demonstrated in cord blood cells, excluding a recall-antigen response. Thus, all of the characteristics of a superantigen-stimulated response are seen, indicating that induction of the EBV lytic cycle is associated with the expression of a superantigen in B cells. A model is presented proposing a role for the superantigen in infection, latency, and oncogenesis.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Accolla R. S., Sekaly R. P., McDonald A. P., Corte G., Gross N., Carrel S. Demonstration at the single-cell level of the existence of distinct clusters of epitopes in two predefined human Ia molecular subsets. Eur J Immunol. 1982 Feb;12(2):166–169. doi: 10.1002/eji.1830120212. [DOI] [PubMed] [Google Scholar]
  2. Astrin S. M., Laurence J. Human immunodeficiency virus activates c-myc and Epstein-Barr virus in human B lymphocytes. Ann N Y Acad Sci. 1992 May 4;651:422–432. doi: 10.1111/j.1749-6632.1992.tb24642.x. [DOI] [PubMed] [Google Scholar]
  3. Baer R., Bankier A. T., Biggin M. D., Deininger P. L., Farrell P. J., Gibson T. J., Hatfull G., Hudson G. S., Satchwell S. C., Séguin C. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature. 1984 Jul 19;310(5974):207–211. doi: 10.1038/310207a0. [DOI] [PubMed] [Google Scholar]
  4. Beutner U., Kraus E., Kitamura D., Rajewsky K., Huber B. T. B cells are essential for murine mammary tumor virus transmission, but not for presentation of endogenous superantigens. J Exp Med. 1994 May 1;179(5):1457–1466. doi: 10.1084/jem.179.5.1457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blank U., Boitel B., Mège D., Ermonval M., Acuto O. Analysis of tetanus toxin peptide/DR recognition by human T cell receptors reconstituted into a murine T cell hybridoma. Eur J Immunol. 1993 Dec;23(12):3057–3065. doi: 10.1002/eji.1830231203. [DOI] [PubMed] [Google Scholar]
  6. Brennan F. M., Allard S., Londei M., Savill C., Boylston A., Carrel S., Maini R. N., Feldmann M. Heterogeneity of T cell receptor idiotypes in rheumatoid arthritis. Clin Exp Immunol. 1988 Sep;73(3):417–423. [PMC free article] [PubMed] [Google Scholar]
  7. Calender A., Billaud M., Aubry J. P., Banchereau J., Vuillaume M., Lenoir G. M. Epstein-Barr virus (EBV) induces expression of B-cell activation markers on in vitro infection of EBV-negative B-lymphoma cells. Proc Natl Acad Sci U S A. 1987 Nov;84(22):8060–8064. doi: 10.1073/pnas.84.22.8060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carrel S., Isler P., Schreyer M., Vacca A., Salvi S., Giuffre L., Mach J. P. Expression on human thymocytes of the idiotypic structures (Ti) from two leukemia T cell lines Jurkat and HPB-ALL. Eur J Immunol. 1986 Jun;16(6):649–652. doi: 10.1002/eji.1830160610. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Choi Y. W., Kotzin B., Lafferty J., White J., Pigeon M., Kubo R., Kappler J., Marrack P. A method for production of antibodies to human T-cell receptor beta-chain variable regions. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8357–8361. doi: 10.1073/pnas.88.19.8357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dobrescu D., Ursea B., Pope M., Asch A. S., Posnett D. N. Enhanced HIV-1 replication in V beta 12 T cells due to human cytomegalovirus in monocytes: evidence for a putative herpesvirus superantigen. Cell. 1995 Sep 8;82(5):753–763. doi: 10.1016/0092-8674(95)90472-7. [DOI] [PubMed] [Google Scholar]
  12. Golovkina T. V., Chervonsky A., Dudley J. P., Ross S. R. Transgenic mouse mammary tumor virus superantigen expression prevents viral infection. Cell. 1992 May 15;69(4):637–645. doi: 10.1016/0092-8674(92)90227-4. [DOI] [PubMed] [Google Scholar]
  13. Hara T., Jung L. K., Bjorndahl J. M., Fu S. M. Human T cell activation. III. Rapid induction of a phosphorylated 28 kD/32 kD disulfide-linked early activation antigen (EA 1) by 12-o-tetradecanoyl phorbol-13-acetate, mitogens, and antigens. J Exp Med. 1986 Dec 1;164(6):1988–2005. doi: 10.1084/jem.164.6.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Held W., Waanders G. A., Shakhov A. N., Scarpellino L., Acha-Orbea H., MacDonald H. R. Superantigen-induced immune stimulation amplifies mouse mammary tumor virus infection and allows virus transmission. Cell. 1993 Aug 13;74(3):529–540. doi: 10.1016/0092-8674(93)80054-i. [DOI] [PubMed] [Google Scholar]
  15. Herman A., Kappler J. W., Marrack P., Pullen A. M. Superantigens: mechanism of T-cell stimulation and role in immune responses. Annu Rev Immunol. 1991;9:745–772. doi: 10.1146/annurev.iy.09.040191.003525. [DOI] [PubMed] [Google Scholar]
  16. Ho H. N., Hultin L. E., Mitsuyasu R. T., Matud J. L., Hausner M. A., Bockstoce D., Chou C. C., O'Rourke S., Taylor J. M., Giorgi J. V. Circulating HIV-specific CD8+ cytotoxic T cells express CD38 and HLA-DR antigens. J Immunol. 1993 Apr 1;150(7):3070–3079. [PubMed] [Google Scholar]
  17. Kappler J. W., Skidmore B., White J., Marrack P. Antigen-inducible, H-2-restricted, interleukin-2-producing T cell hybridomas. Lack of independent antigen and H-2 recognition. J Exp Med. 1981 May 1;153(5):1198–1214. doi: 10.1084/jem.153.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Khanna R., Burrows S. R., Moss D. J. Immune regulation in Epstein-Barr virus-associated diseases. Microbiol Rev. 1995 Sep;59(3):387–405. doi: 10.1128/mr.59.3.387-405.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lauener R. P., Hüttner S., Buisson M., Hossle J. P., Albisetti M., Seigneurin J. M., Seger R. A., Nadal D. T-cell death by apoptosis in vertically human immunodeficiency virus-infected children coincides with expansion of CD8+/interleukin-2 receptor-/HLA-DR+ T cells: sign of a possible role for herpes viruses as cofactors? Blood. 1995 Aug 15;86(4):1400–1407. [PubMed] [Google Scholar]
  20. Le Bon A., Desaymard C., Papiernik M. Neonatal impaired response to viral superantigen encoded by MMTV(SW) and Mtv-7. Int Immunol. 1995 Dec;7(12):1897–1903. doi: 10.1093/intimm/7.12.1897. [DOI] [PubMed] [Google Scholar]
  21. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lewis D. E., Tang D. S., Adu-Oppong A., Schober W., Rodgers J. R. Anergy and apoptosis in CD8+ T cells from HIV-infected persons. J Immunol. 1994 Jul 1;153(1):412–420. [PubMed] [Google Scholar]
  23. Long E. O., Rosen-Bronson S., Karp D. R., Malnati M., Sekaly R. P., Jaraquemada D. Efficient cDNA expression vectors for stable and transient expression of HLA-DR in transfected fibroblast and lymphoid cells. Hum Immunol. 1991 Aug;31(4):229–235. doi: 10.1016/0198-8859(91)90092-n. [DOI] [PubMed] [Google Scholar]
  24. Lukacher A. E., Ma Y., Carroll J. P., Abromson-Leeman S. R., Laning J. C., Dorf M. E., Benjamin T. L. Susceptibility to tumors induced by polyoma virus is conferred by an endogenous mouse mammary tumor virus superantigen. J Exp Med. 1995 May 1;181(5):1683–1692. doi: 10.1084/jem.181.5.1683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Miller G., Lipman M. Release of infectious Epstein-Barr virus by transformed marmoset leukocytes. Proc Natl Acad Sci U S A. 1973 Jan;70(1):190–194. doi: 10.1073/pnas.70.1.190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Miyashita E. M., Yang B., Lam K. M., Crawford D. H., Thorley-Lawson D. A. A novel form of Epstein-Barr virus latency in normal B cells in vivo. Cell. 1995 Feb 24;80(4):593–601. doi: 10.1016/0092-8674(95)90513-8. [DOI] [PubMed] [Google Scholar]
  28. Moss D. J., Burrows S. R., Baxter G. D., Lavin M. F. T cell-T cell killing is induced by specific epitopes: evidence for an apoptotic mechanism. J Exp Med. 1991 Mar 1;173(3):681–686. doi: 10.1084/jem.173.3.681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Moss D. J., Rickinson A. B., Pope J. H. Long-term T-cell-mediated immunity to Epstein-Barr virus in man. I. Complete regression of virus-induced transformation in cultures of seropositive donor leukocytes. Int J Cancer. 1978 Dec;22(6):662–668. doi: 10.1002/ijc.2910220604. [DOI] [PubMed] [Google Scholar]
  30. Posnett D. N., Bigler R. D., Bushkin Y., Fisher D. E., Wang C. Y., Mayer L. F., Chiorazzi N., Kunkel H. G. T cell antiidiotypic antibodies reveal differences between two human leukemias. J Exp Med. 1984 Aug 1;160(2):494–505. doi: 10.1084/jem.160.2.494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Posnett D. N., Gottlieb A., Bussel J. B., Friedman S. M., Chiorazzi N., Li Y., Szabo P., Farid N. R., Robinson M. A. T cell antigen receptors in autoimmunity. J Immunol. 1988 Sep 15;141(6):1963–1969. [PubMed] [Google Scholar]
  32. Rebai N., Pantaleo G., Demarest J. F., Ciurli C., Soudeyns H., Adelsberger J. W., Vaccarezza M., Walker R. E., Sekaly R. P., Fauci A. S. Analysis of the T-cell receptor beta-chain variable-region (V beta) repertoire in monozygotic twins discordant for human immunodeficiency virus: evidence for perturbations of specific V beta segments in CD4+ T cells of the virus-positive twins. Proc Natl Acad Sci U S A. 1994 Feb 15;91(4):1529–1533. doi: 10.1073/pnas.91.4.1529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rochford R., Mosier D. E. Differential Epstein-Barr virus gene expression in B-cell subsets recovered from lymphomas in SCID mice after transplantation of human peripheral blood lymphocytes. J Virol. 1995 Jan;69(1):150–155. doi: 10.1128/jvi.69.1.150-155.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Saito I., Servenius B., Compton T., Fox R. I. Detection of Epstein-Barr virus DNA by polymerase chain reaction in blood and tissue biopsies from patients with Sjogren's syndrome. J Exp Med. 1989 Jun 1;169(6):2191–2198. doi: 10.1084/jem.169.6.2191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sumida T., Sakamaki T., Yonaha F., Maeda T., Namekawa T., Nawata Y., Takabayashi K., Iwamoto I., Yoshida S. HLA-DR alleles in patients with Sjögren's syndrome over-representing V beta 2 and V beta 13 genes in the labial salivary glands. Br J Rheumatol. 1994 May;33(5):420–424. doi: 10.1093/rheumatology/33.5.420. [DOI] [PubMed] [Google Scholar]
  36. Takahashi S., Maecker H. T., Levy R. DNA fragmentation and cell death mediated by T cell antigen receptor/CD3 complex on a leukemia T cell line. Eur J Immunol. 1989 Oct;19(10):1911–1919. doi: 10.1002/eji.1830191023. [DOI] [PubMed] [Google Scholar]
  37. Testi R., Phillips J. H., Lanier L. L. Leu 23 induction as an early marker of functional CD3/T cell antigen receptor triggering. Requirement for receptor cross-linking, prolonged elevation of intracellular [Ca++] and stimulation of protein kinase C. J Immunol. 1989 Mar 15;142(6):1854–1860. [PubMed] [Google Scholar]
  38. Thorley-Lawson D. A., Chess L., Strominger J. L. Suppression of in vitro Epstein-Barr virus infection. A new role for adult human T lymphocytes. J Exp Med. 1977 Aug 1;146(2):495–508. doi: 10.1084/jem.146.2.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tomkinson B. E., Maziarz R., Sullivan J. L. Characterization of the T cell-mediated cellular cytotoxicity during acute infectious mononucleosis. J Immunol. 1989 Jul 15;143(2):660–670. [PubMed] [Google Scholar]
  40. Uehara T., Miyawaki T., Ohta K., Tamaru Y., Yokoi T., Nakamura S., Taniguchi N. Apoptotic cell death of primed CD45RO+ T lymphocytes in Epstein-Barr virus-induced infectious mononucleosis. Blood. 1992 Jul 15;80(2):452–458. [PubMed] [Google Scholar]
  41. Van Kuyk R., Mosier D. E. Lack of pseudotype formation between human immunodeficiency virus type 1 and Epstein-Barr virus in productively coinfected B lymphoblastoid cell lines. Virology. 1995 Jun 1;209(2):643–648. doi: 10.1006/viro.1995.1297. [DOI] [PubMed] [Google Scholar]
  42. Veronese M. L., Veronesi A., Bruni L., Coppola V., D'Andrea E., Del Mistro A., Mezzalira S., Montagna M., Ruffatto G., Amadori A. Properties of tumors arising in SCID mice injected with PBMC from EBV-positive donors. Leukemia. 1994 Apr;8 (Suppl 1):S214–S217. [PubMed] [Google Scholar]
  43. Veronese M. L., Veronesi A., D'Andrea E., Del Mistro A., Indraccolo S., Mazza M. R., Mion M., Zamarchi R., Menin C., Panozzo M. Lymphoproliferative disease in human peripheral blood mononuclear cell-injected SCID mice. I. T lymphocyte requirement for B cell tumor generation. J Exp Med. 1992 Dec 1;176(6):1763–1767. doi: 10.1084/jem.176.6.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Veronesi A., Coppola V., Veronese M. L., Menin C., Bruni L., D'Andrea E., Mion M., Amadori A., Chieco-Bianchi L. Lymphoproliferative disease in human peripheral-blood-mononuclear-cell- injected scid mice. II. Role of host and donor factors in tumor generation. Int J Cancer. 1994 Dec 1;59(5):676–683. doi: 10.1002/ijc.2910590516. [DOI] [PubMed] [Google Scholar]
  45. Waller E. K., Sen-Majumdar A., Kamel O. W., Hansteen G. A., Schick M. R., Weissman I. L. Human T-cell development in SCID-hu mice: staphylococcal enterotoxins induce specific clonal deletions, proliferation, and anergy. Blood. 1992 Dec 15;80(12):3144–3156. [PubMed] [Google Scholar]
  46. Wei S., Charmley P., Robinson M. A., Concannon P. The extent of the human germline T-cell receptor V beta gene segment repertoire. Immunogenetics. 1994;40(1):27–36. doi: 10.1007/BF00163961. [DOI] [PubMed] [Google Scholar]
  47. Yonaha F., Sumida T., Maeda T., Tomioka H., Koike T., Yoshida S. Restricted junctional usage of T cell receptor V beta 2 and V beta 13 genes, which are overrepresented on infiltrating T cells in the lips of patients with Sjögren's syndrome. Arthritis Rheum. 1992 Nov;35(11):1362–1367. doi: 10.1002/art.1780351118. [DOI] [PubMed] [Google Scholar]
  48. von Knebel Doeberitz M., Bornkamm G. W., zur Hausen H. Establishment of spontaneously outgrowing lymphoblastoid cell lines with Cyclosporin A. Med Microbiol Immunol. 1983;172(2):87–99. doi: 10.1007/BF02124509. [DOI] [PubMed] [Google Scholar]
  49. zur Hausen H., O'Neill F. J., Freese U. K., Hecker E. Persisting oncogenic herpesvirus induced by the tumour promotor TPA. Nature. 1978 Mar 23;272(5651):373–375. doi: 10.1038/272373a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES