Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Feb 1;177(2):359–366. doi: 10.1084/jem.177.2.359

Superantigen-reactive CD4+ T cells are required to stimulate B cells after infection with mouse mammary tumor virus

PMCID: PMC2190911  PMID: 8093892

Abstract

Superantigens are defined by their ability to stimulate a large fraction of T cells via interaction with the T cell receptor (TCR) V beta domain. Endogenous superantigens, classically termed minor lymphocyte-stimulating (Mls) antigens, were recently identified as products of open reading frames (ORF) in integrated proviral copies of mouse mammary tumor virus (MMTV). We have described an infectious MMTV homologue of the classical endogenous superantigen Mls-1a (Mtv-7). The ORF molecules of both the endogenous Mtv-7 and the infectious MMTV(SW) interact with T cells expressing the TCR V beta 6, 7, 8.1, and 9 domains. Furthermore, the COOH termini of their ORF molecules, thought to confer TCR specificity, are very similar. Since successful transport of MMTV from the site of infection in the gut to the mammary gland depends on a functional immune system, we were interested in determining the early events after and requirements for MMTV infection. We show that MMTV(SW) infection induces a massive response of V beta 6+ CDC4+ T cells, which interact with the viral ORF. Concomitantly, we observed a B cell response and differentiation that depends on both the presence and stimulation of the superantigen-reactive T cells. Furthermore, we show that B cells are the main target of the initial MMTV infection as judged by the presence of the reverse-transcribed viral genome and ORF transcripts. Thus, we suggest that MMTV infection of B cells leads to ORF-mediated B-T cell interaction, which maintains and possibly amplifies viral infection.

Full Text

The Full Text of this article is available as a PDF (918.7 KB).

Selected References

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

  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. Acha-Orbea H., Palmer E. Mls--a retrovirus exploits the immune system. Immunol Today. 1991 Oct;12(10):356–361. doi: 10.1016/0167-5699(91)90066-3. [DOI] [PubMed] [Google Scholar]
  3. Acha-Orbea H., Shakhov A. N., Scarpellino L., Kolb E., Müller V., Vessaz-Shaw A., Fuchs R., Blöchlinger K., Rollini P., Billotte J. Clonal deletion of V beta 14-bearing T cells in mice transgenic for mammary tumour virus. Nature. 1991 Mar 21;350(6315):207–211. doi: 10.1038/350207a0. [DOI] [PubMed] [Google Scholar]
  4. Augustin A. A., Coutinho A. Specific T helper cells that activate B cells polyclonally. In vitro enrichment and cooperative function. J Exp Med. 1980 Mar 1;151(3):587–601. doi: 10.1084/jem.151.3.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bandeira A., Mengel J., Burlen-Defranoux O., Coutinho A. Proliferative T cell anergy to MIs-1a does not correlate with in vivo tolerance. Int Immunol. 1991 Sep;3(9):923–931. doi: 10.1093/intimm/3.9.923. [DOI] [PubMed] [Google Scholar]
  6. Beutner U., Frankel W. N., Cote M. S., Coffin J. M., Huber B. T. Mls-1 is encoded by the long terminal repeat open reading frame of the mouse mammary tumor provirus Mtv-7. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5432–5436. doi: 10.1073/pnas.89.12.5432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Choi Y., Kappler J. W., Marrack P. A superantigen encoded in the open reading frame of the 3' long terminal repeat of mouse mammary tumour virus. Nature. 1991 Mar 21;350(6315):203–207. doi: 10.1038/350203a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Dialynas D. P., Wilde D. B., Marrack P., Pierres A., Wall K. A., Havran W., Otten G., Loken M. R., Pierres M., Kappler J. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol Rev. 1983;74:29–56. doi: 10.1111/j.1600-065x.1983.tb01083.x. [DOI] [PubMed] [Google Scholar]
  10. Fasel N., Buetti E., Firzlaff J., Pearson K., Diggelmann H. Nucleotide sequence of the 5' noncoding region and part of the gag gene of mouse mammary tumor virus; identification of the 5' splicing site for subgenomic mRNAs. Nucleic Acids Res. 1983 Oct 25;11(20):6943–6955. doi: 10.1093/nar/11.20.6943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Festenstein H., Berumen L. BALB.D2-Mlsa--a new congenic mouse strain. Transplantation. 1984 Mar;37(3):322–324. doi: 10.1097/00007890-198403000-00024. [DOI] [PubMed] [Google Scholar]
  12. Gajewski T. F., Schell S. R., Nau G., Fitch F. W. Regulation of T-cell activation: differences among T-cell subsets. Immunol Rev. 1989 Oct;111:79–110. doi: 10.1111/j.1600-065x.1989.tb00543.x. [DOI] [PubMed] [Google Scholar]
  13. Gaugler B., Langlet C., Martin J. M., Schmitt-Verhulst A. M., Guimezanes A. Evidence for quantitative and qualitative differences in functional activation of Mls-reactive T cell clones and hybridomas by antigen or TcR/CD3 antibodies. Eur J Immunol. 1991 Oct;21(10):2581–2589. doi: 10.1002/eji.1830211040. [DOI] [PubMed] [Google Scholar]
  14. Glasebrook A. L., Quintans J., Eisenberg L., Fitch F. W. Alloreactive cloned T cell lines. II. Polyclonal stimulation of B cells by a cloned helper T cell line. J Immunol. 1981 Jan;126(1):240–244. [PubMed] [Google Scholar]
  15. 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]
  16. Happ M. P., Woodland D. L., Palmer E. A third T-cell receptor beta-chain variable region gene encodes reactivity to Mls-1a gene products. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6293–6296. doi: 10.1073/pnas.86.16.6293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Held W., Shakhov A. N., Waanders G., Scarpellino L., Luethy R., Kraehenbuhl J. P., MacDonald H. R., Acha-Orbea H. An exogenous mouse mammary tumor virus with properties of Mls-1a (Mtv-7). J Exp Med. 1992 Jun 1;175(6):1623–1633. doi: 10.1084/jem.175.6.1623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
  19. Liao N. S., Maltzman J., Raulet D. H. Positive selection determines T cell receptor V beta 14 gene usage by CD8+ T cells. J Exp Med. 1989 Jul 1;170(1):135–143. doi: 10.1084/jem.170.1.135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lund F. E., Corley R. B. Regulated expression of mouse mammary tumor proviral genes in cells of the B lineage. J Exp Med. 1991 Dec 1;174(6):1439–1450. doi: 10.1084/jem.174.6.1439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. MacDonald H. R., Glasebrook A. L., Schneider R., Lees R. K., Pircher H., Pedrazzini T., Kanagawa O., Nicolas J. F., Howe R. C., Zinkernagel R. M. T-cell reactivity and tolerance to Mlsa-encoded antigens. Immunol Rev. 1989 Feb;107:89–108. doi: 10.1111/j.1600-065x.1989.tb00004.x. [DOI] [PubMed] [Google Scholar]
  22. Okada C. Y., Holzmann B., Guidos C., Palmer E., Weissman I. L. Characterization of a rat monoclonal antibody specific for a determinant encoded by the V beta 7 gene segment. Depletion of V beta 7+ T cells in mice with Mls-1a haplotype. J Immunol. 1990 May 1;144(9):3473–3477. [PubMed] [Google Scholar]
  23. Parham P. Typing for class I HLA polymorphism: past, present, and future. Eur J Immunogenet. 1992 Oct;19(5):347–359. doi: 10.1111/j.1744-313x.1992.tb00078.x. [DOI] [PubMed] [Google Scholar]
  24. Payne J., Huber B. T., Cannon N. A., Schneider R., Schilham M. W., Acha-Orbea H., MacDonald H. R., Hengartner H. Two monoclonal rat antibodies with specificity for the beta-chain variable region V beta 6 of the murine T-cell receptor. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7695–7698. doi: 10.1073/pnas.85.20.7695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pereira P., Rocha B. Post- thymic in vivo expansion of mature alpha beta T cells. Int Immunol. 1991 Nov;3(11):1077–1080. doi: 10.1093/intimm/3.11.1077. [DOI] [PubMed] [Google Scholar]
  26. Racevskis J. Altered mouse mammary tumor virus transcript synthesis in T-cell lymphoma cells. J Virol. 1990 Sep;64(9):4043–4050. doi: 10.1128/jvi.64.9.4043-4050.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sarmiento M., Dialynas D. P., Lancki D. W., Wall K. A., Lorber M. I., Loken M. R., Fitch F. W. Cloned T lymphocytes and monoclonal antibodies as probes for cell surface molecules active in T cell-mediated cytolysis. Immunol Rev. 1982;68:135–169. doi: 10.1111/j.1600-065x.1982.tb01063.x. [DOI] [PubMed] [Google Scholar]
  28. Schneider R., Lees R. K., Pedrazzini T., Zinkernagel R. M., Hengartner H., MacDonald H. R. Postnatal disappearance of self-reactive (V beta 6+) cells from the thymus of Mlsa mice. Implications for T cell development and autoimmunity. J Exp Med. 1989 Jun 1;169(6):2149–2158. doi: 10.1084/jem.169.6.2149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schurmans S., Brighouse G., Kramer G., Wen L., Izui S., Merino J., Lambert P. H. Transient T and B cell activation after neonatal induction of tolerance to MHC class II or Mls alloantigens. J Immunol. 1991 Apr 1;146(7):2152–2160. [PubMed] [Google Scholar]
  30. Schurmans S., Heusser C. H., Qin H. Y., Merino J., Brighouse G., Lambert P. H. In vivo effects of anti-IL-4 monoclonal antibody on neonatal induction of tolerance and on an associated autoimmune syndrome. J Immunol. 1990 Oct 15;145(8):2465–2473. [PubMed] [Google Scholar]
  31. Smith G. H., Young L. J., Benjamini F., Medina D., Cardiff R. D. Proteins antigenically related to peptides encoded by the mouse mammary tumour virus long terminal repeat sequence are associated with intracytoplasmic A particles. J Gen Virol. 1987 Feb;68(Pt 2):473–486. doi: 10.1099/0022-1317-68-2-473. [DOI] [PubMed] [Google Scholar]
  32. Snapper C. M., Paul W. E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987 May 22;236(4804):944–947. doi: 10.1126/science.3107127. [DOI] [PubMed] [Google Scholar]
  33. Squartini F., Olivi M., Bolis G. B. Mouse strain and breeding stimulation as factors influencing the effect of thymectomy on mammary tumorigenesis. Cancer Res. 1970 Jul;30(7):2069–2072. [PubMed] [Google Scholar]
  34. Staerz U. D., Rammensee H. G., Benedetto J. D., Bevan M. J. Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor. J Immunol. 1985 Jun;134(6):3994–4000. [PubMed] [Google Scholar]
  35. Tsubura A., Inaba M., Imai S., Murakami A., Oyaizu N., Yasumizu R., Ohnishi Y., Tanaka H., Morii S., Ikehara S. Intervention of T-cells in transportation of mouse mammary tumor virus (milk factor) to mammary gland cells in vivo. Cancer Res. 1988 Nov 15;48(22):6555–6559. [PubMed] [Google Scholar]
  36. Woodland D. L., Lund F. E., Happ M. P., Blackman M. A., Palmer E., Corley R. B. Endogenous superantigen expression is controlled by mouse mammary tumor proviral loci. J Exp Med. 1991 Nov 1;174(5):1255–1258. doi: 10.1084/jem.174.5.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. van Ooyen A. J., Michalides R. J., Nusse R. Structural analysis of a 1.7-kilobase mouse mammary tumor virus-specific RNA. J Virol. 1983 May;46(2):362–370. doi: 10.1128/jvi.46.2.362-370.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES