Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 May 1;179(5):1457–1466. doi: 10.1084/jem.179.5.1457

B cells are essential for murine mammary tumor virus transmission, but not for presentation of endogenous superantigens

PMCID: PMC2191484  PMID: 8163931

Abstract

Murine mammary tumor viruses (MMTVs) are retroviruses that encode superantigens capable of stimulating T cells via superantigen-reactive T cell receptor V beta chains. MMTVs are transmitted to the suckling offspring through milk. Here we show that B cell-deficient mice foster nursed by virus-secreting mice do not transfer infectious MMTVs to their offspring. No MMTV proviruses could be detected in the spleen and mammary tissue of these mice, and no deletion of MMTV superantigen- reactive T cells occurred. By contrast, T cell deletion and positive selection due to endogenous MMTV superantigens occurred in B cell- deficient mice. We conclude that B cells are essential for the completion of the viral life cycle in vivo, but that endogenous MMTV superantigens can be presented by cell types other than B cells.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

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

  1. Ahmed A., Scher I., Smith A. H., Sell K. W. Studies on non-H-2 linked lymphocyte activating determinants. I. Description of the cell type bearing the Mls product. J Immunogenet. 1977 Jun;4(3):201–213. doi: 10.1111/j.1744-313x.1977.tb00902.x. [DOI] [PubMed] [Google Scholar]
  2. Bandeira A., Coutinho A., Burlen-Defranoux O., Khazaal I., Coltey M., Jacquemart F., Le Douarin N., Salaün J. Thymic epithelium induces neither clonal deletion nor anergy to Mls 1a antigens. Eur J Immunol. 1992 Jun;22(6):1397–1404. doi: 10.1002/eji.1830220611. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Beutner U., Rudy C., Huber B. T. Molecular characterization of Mls-1. Int Rev Immunol. 1992;8(4):279–288. doi: 10.3109/08830189209053513. [DOI] [PubMed] [Google Scholar]
  5. Bill J., Kanagawa O., Linten J., Utsunomiya Y., Palmer E. Class I and class II MHC gene products differentially affect the fate of V beta 5 bearing thymocytes. J Mol Cell Immunol. 1990;4(5):269–280. [PubMed] [Google Scholar]
  6. Bill J., Kanagawa O., Woodland D. L., Palmer E. The MHC molecule I-E is necessary but not sufficient for the clonal deletion of V beta 11-bearing T cells. J Exp Med. 1989 Apr 1;169(4):1405–1419. doi: 10.1084/jem.169.4.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brandt-Carlson C., Butel J. S., Wheeler D. Phylogenetic and structural analyses of MMTV LTR ORF sequences of exogenous and endogenous origins. Virology. 1993 Mar;193(1):171–185. doi: 10.1006/viro.1993.1113. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. Coffman R. L. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development. Immunol Rev. 1982;69:5–23. doi: 10.1111/j.1600-065x.1983.tb00446.x. [DOI] [PubMed] [Google Scholar]
  10. Cohen J. C., Varmus H. E. Endogenous mammary tumour virus DNA varies among wild mice and segregates during inbreeding. Nature. 1979 Mar 29;278(5703):418–423. doi: 10.1038/278418a0. [DOI] [PubMed] [Google Scholar]
  11. Dyson P. J., Knight A. M., Fairchild S., Simpson E., Tomonari K. Genes encoding ligands for deletion of V beta 11 T cells cosegregate with mammary tumour virus genomes. Nature. 1991 Feb 7;349(6309):531–532. doi: 10.1038/349531a0. [DOI] [PubMed] [Google Scholar]
  12. Faro J., Marcos M. A., Andreu J. L., Martinez-A C., Coutinho A. Inside the thymus, Mls antigen is exclusively presented by B lymphocytes. Res Immunol. 1990 Oct;141(8):723–737. doi: 10.1016/0923-2494(90)90003-h. [DOI] [PubMed] [Google Scholar]
  13. Frankel W. N., Rudy C., Coffin J. M., Huber B. T. Linkage of Mls genes to endogenous mammary tumour viruses of inbred mice. Nature. 1991 Feb 7;349(6309):526–528. doi: 10.1038/349526a0. [DOI] [PubMed] [Google Scholar]
  14. Gollob K. J., Palmer E. Aberrant induction of T cell tolerance in B cell suppressed mice. J Immunol. 1993 May 1;150(9):3705–3712. [PubMed] [Google Scholar]
  15. Gollob K. J., Palmer E. Physiologic expression of two superantigens in the BDF1 mouse. J Immunol. 1991 Oct 15;147(8):2447–2454. [PubMed] [Google Scholar]
  16. 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]
  17. Grusby M. J., Johnson R. S., Papaioannou V. E., Glimcher L. H. Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice. Science. 1991 Sep 20;253(5026):1417–1420. doi: 10.1126/science.1910207. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Held W., Shakhov A. N., Izui S., Waanders G. A., Scarpellino L., MacDonald H. R., Acha-Orbea H. Superantigen-reactive CD4+ T cells are required to stimulate B cells after infection with mouse mammary tumor virus. J Exp Med. 1993 Feb 1;177(2):359–366. doi: 10.1084/jem.177.2.359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Ignatowicz L., Kappler J., Marrack P. The effects of chronic infection with a superantigen-producing virus. J Exp Med. 1992 Apr 1;175(4):917–923. doi: 10.1084/jem.175.4.917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Inaba M., Inaba K., Hosono M., Kumamoto T., Ishida T., Muramatsu S., Masuda T., Ikehara S. Distinct mechanisms of neonatal tolerance induced by dendritic cells and thymic B cells. J Exp Med. 1991 Mar 1;173(3):549–559. doi: 10.1084/jem.173.3.549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kitamura D., Roes J., Kühn R., Rajewsky K. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature. 1991 Apr 4;350(6317):423–426. doi: 10.1038/350423a0. [DOI] [PubMed] [Google Scholar]
  25. Kühn R., Rajewsky K., Müller W. Generation and analysis of interleukin-4 deficient mice. Science. 1991 Nov 1;254(5032):707–710. doi: 10.1126/science.1948049. [DOI] [PubMed] [Google Scholar]
  26. Liao N. S., Raulet D. H. Expression of the Mls-1a superantigen results in an increased frequency of V beta 14+ T cells. J Immunol. 1992 Aug 15;149(4):1151–1155. [PubMed] [Google Scholar]
  27. Liegler T. J., Blair P. B. Direct detection of exogenous mouse mammary tumor virus sequences in lymphoid cells of BALB/cfC3H female mice. J Virol. 1986 Jul;59(1):159–162. doi: 10.1128/jvi.59.1.159-162.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lund F. E., Randall T. D., Woodland D. L., Corley R. B. MHC class II limits the functional expression of endogenous superantigens in B cells. J Immunol. 1993 Jan 1;150(1):78–86. [PubMed] [Google Scholar]
  29. Majors J. E., Varmus H. E. Nucleotide sequencing of an apparent proviral copy of env mRNA defines determinants of expression of the mouse mammary tumor virus env gene. J Virol. 1983 Sep;47(3):495–504. doi: 10.1128/jvi.47.3.495-504.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Marcu K. B., Banerji J., Penncavage N. A., Lang R., Arnheim N. 5' flanking region of immunoglobulin heavy chain constant region genes displays length heterogeneity in germlines of inbred mouse strains. Cell. 1980 Nov;22(1 Pt 1):187–196. doi: 10.1016/0092-8674(80)90167-1. [DOI] [PubMed] [Google Scholar]
  31. Marrack P., Kushnir E., Kappler J. A maternally inherited superantigen encoded by a mammary tumour virus. Nature. 1991 Feb 7;349(6309):524–526. doi: 10.1038/349524a0. [DOI] [PubMed] [Google Scholar]
  32. Mazda O., Watanabe Y., Gyotoku J., Katsura Y. Requirement of dendritic cells and B cells in the clonal deletion of Mls-reactive T cells in the thymus. J Exp Med. 1991 Mar 1;173(3):539–547. doi: 10.1084/jem.173.3.539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Molina I. J., Cannon N. A., Hyman R., Huber B. T. Macrophages and T cells do not express Mlsa determinants. J Immunol. 1989 Jul 1;143(1):39–44. [PubMed] [Google Scholar]
  34. 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]
  35. Papiernik M., Pontoux C., Gisselbrecht S. Acquired Mls-1a-like clonal deletion in Mls-1b mice. J Exp Med. 1992 Feb 1;175(2):453–460. doi: 10.1084/jem.175.2.453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Rudy C. K., Kraus E., Palmer E., Huber B. T. Mls-1-like superantigen in the MA/MyJ mouse is encoded by a new mammary tumor provirus that is distinct from Mtv-7. J Exp Med. 1992 Jun 1;175(6):1613–1621. doi: 10.1084/jem.175.6.1613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Salaün J., Bandeira A., Khazaal I., Burlen-Defranoux O., Thomas-Vaslin V., Coltey M., Le Douarin N. M., Coutinho A. Transplantation tolerance is unrelated to superantigen-dependent deletion and anergy. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10420–10424. doi: 10.1073/pnas.89.21.10420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Salmons B., Günzburg W. H. Current perspectives in the biology of mouse mammary tumour virus. Virus Res. 1987 Aug;8(2):81–102. doi: 10.1016/0168-1702(87)90022-0. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. 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]
  42. Utsunomiya Y., Kosaka H., Kanagawa O. Differential reactivity of V beta 9 T cells to minor lymphocyte stimulating antigen in vitro and in vivo. Eur J Immunol. 1991 Apr;21(4):1007–1011. doi: 10.1002/eji.1830210422. [DOI] [PubMed] [Google Scholar]
  43. Waanders G. A., Shakhov A. N., Held W., Karapetian O., Acha-Orbea H., MacDonald H. R. Peripheral T cell activation and deletion induced by transfer of lymphocyte subsets expressing endogenous or exogenous mouse mammary tumor virus. J Exp Med. 1993 May 1;177(5):1359–1366. doi: 10.1084/jem.177.5.1359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Webb S. R., Okamoto A., Ron Y., Sprent J. Restricted tissue distribution of Mlsa determinants. Stimulation of Mlsa-reactive T cells by B cells but not by dendritic cells or macrophages. J Exp Med. 1989 Jan 1;169(1):1–12. doi: 10.1084/jem.169.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Webb S. R., Sprent J. Induction of neonatal tolerance to Mlsa antigens by CD8+ T cells. Science. 1990 Jun 29;248(4963):1643–1646. doi: 10.1126/science.1973003. [DOI] [PubMed] [Google Scholar]
  46. Woodland D. L., Happ M. P., Gollob K. J., Palmer E. An endogenous retrovirus mediating deletion of alpha beta T cells? Nature. 1991 Feb 7;349(6309):529–530. doi: 10.1038/349529a0. [DOI] [PubMed] [Google Scholar]
  47. Woodland D., Happ M. P., Bill J., Palmer E. Requirement for cotolerogenic gene products in the clonal deletion of I-E reactive T cells. Science. 1990 Feb 23;247(4945):964–967. doi: 10.1126/science.1968289. [DOI] [PubMed] [Google Scholar]

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

RESOURCES