Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1997 Feb;71(2):1237–1245. doi: 10.1128/jvi.71.2.1237-1245.1997

Shared promoter elements between a viral superantigen and the major histocompatibility complex class II-associated invariant chain.

J Arroyo 1, E Winchester 1, B S McLellan 1, B T Huber 1
PMCID: PMC191178  PMID: 8995647

Abstract

Superantigens have the ability to stimulate subsets of T lymphocytes bearing particular T-cell receptor Vbeta chains. The best-known viral superantigen is Mls, a product of the murine mammary tumor virus (MMTV) sag gene. The MMTV superantigen is not displayed by the virus itself; however, after infection of B lymphocytes, the superantigen is expressed. The resulting immune stimulation is essential for viral transmission. We have analyzed the transcriptional elements which control Mls-1 expression. Here we present evidence that a region at the 3' end of Mtv-7 env, Penv2, controls B-cell-specific expression of sag. Penv2 has elements homologous with promoters of immunoglobulin H chain, the invariant chain, and major histocompatibility complex class II, suggesting a coordinate regulation of expression of these various B-cell-specific genes and indicating a possible eukaryotic origin of MMTV sag. We have determined that both an IgH heptamer element and a Y box are essential for Penv2 promoter activity and that tandem octamer motifs in the U3 region of the 3' MMTV long terminal repeat function as enhancers. We propose that Penv2 controls constitutive Mls expression in B lymphocytes.

Full Text

The Full Text of this article is available as a PDF (407.3 KB).

Selected References

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

  1. Acha-Orbea H., MacDonald H. R. Superantigens of mouse mammary tumor virus. Annu Rev Immunol. 1995;13:459–486. doi: 10.1146/annurev.iy.13.040195.002331. [DOI] [PubMed] [Google Scholar]
  2. Basta P. V., Sherman P. A., Ting J. P. Detailed delineation of an interferon-gamma-responsive element important in human HLA-DRA gene expression in a glioblastoma multiform line. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8618–8622. doi: 10.1073/pnas.85.22.8618. [DOI] [PMC free article] [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., 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. Brown A. M., Wright K. L., Ting J. P. Human major histocompatibility complex class II-associated invariant chain gene promoter. Functional analysis and in vivo protein/DNA interactions of constitutive and IFN-gamma-induced expression. J Biol Chem. 1993 Dec 15;268(35):26328–26333. [PubMed] [Google Scholar]
  6. Buetti E. Stably integrated mouse mammary tumor virus long terminal repeat DNA requires the octamer motifs for basal promoter activity. Mol Cell Biol. 1994 Feb;14(2):1191–1203. doi: 10.1128/mcb.14.2.1191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cavin C., Buetti E. Tissue-specific and ubiquitous factors binding next to the glucocorticoid receptor modulate transcription from the mouse mammary tumor virus promoter. J Virol. 1995 Jun;69(6):3759–3770. doi: 10.1128/jvi.69.6.3759-3770.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chang C. H., Guerder S., Hong S. C., van Ewijk W., Flavell R. A. Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity. 1996 Feb;4(2):167–178. doi: 10.1016/s1074-7613(00)80681-0. [DOI] [PubMed] [Google Scholar]
  9. Corley R. B., Lund F. E., Randall T. D., King L. B., Doerre S., Woodland D. L. Mouse mammary tumor proviral gene expression in cells of the B lineage. Semin Immunol. 1992 Oct;4(5):287–296. [PubMed] [Google Scholar]
  10. Cresswell P. Assembly, transport, and function of MHC class II molecules. Annu Rev Immunol. 1994;12:259–293. doi: 10.1146/annurev.iy.12.040194.001355. [DOI] [PubMed] [Google Scholar]
  11. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  12. Dellabona P., Peccoud J., Kappler J., Marrack P., Benoist C., Mathis D. Superantigens interact with MHC class II molecules outside of the antigen groove. Cell. 1990 Sep 21;62(6):1115–1121. doi: 10.1016/0092-8674(90)90388-u. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Eades A. M., Litfin M., Rahmsdorf H. J. The IFN-gamma response of the murine invariant chain gene is mediated by a complex enhancer that includes several MHC class II consensus elements. J Immunol. 1990 Jun 1;144(11):4399–4409. [PubMed] [Google Scholar]
  15. Farrar J. J., Fuller-Farrar J., Simon P. L., Hilfiker M. L., Stadler B. M., Farrar W. L. Thymoma production of T cell growth factor (Interleukin 2). J Immunol. 1980 Dec;125(6):2555–2558. [PubMed] [Google Scholar]
  16. Festenstein H. Immunogenetic and biological aspects of in vitro lymphocyte allotransformation (MLR) in the mouse. Transplant Rev. 1973;15:62–88. doi: 10.1111/j.1600-065x.1973.tb00111.x. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. Glimcher L. H., Kara C. J. Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol. 1992;10:13–49. doi: 10.1146/annurev.iy.10.040192.000305. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Günzburg W. H., Heinemann F., Wintersperger S., Miethke T., Wagner H., Erfle V., Salmons B. Endogenous superantigen expression controlled by a novel promoter in the MMTV long terminal repeat. Nature. 1993 Jul 8;364(6433):154–158. doi: 10.1038/364154a0. [DOI] [PubMed] [Google Scholar]
  22. Günzburg W. H., Salmons B. Factors controlling the expression of mouse mammary tumour virus. Biochem J. 1992 May 1;283(Pt 3):625–632. doi: 10.1042/bj2830625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. 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]
  26. Herman A., Croteau G., Sekaly R. P., Kappler J., Marrack P. HLA-DR alleles differ in their ability to present staphylococcal enterotoxins to T cells. J Exp Med. 1990 Sep 1;172(3):709–717. doi: 10.1084/jem.172.3.709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hyman R., Stallings V. Complementation patterns of Thy-1 variants and evidence that antigen loss variants "pre-exist" in the parental population. J Natl Cancer Inst. 1974 Feb;52(2):429–436. doi: 10.1093/jnci/52.2.429. [DOI] [PubMed] [Google Scholar]
  28. Jainchill J. L., Aaronson S. A., Todaro G. J. Murine sarcoma and leukemia viruses: assay using clonal lines of contact-inhibited mouse cells. J Virol. 1969 Nov;4(5):549–553. doi: 10.1128/jvi.4.5.549-553.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kappler J. W., Staerz U., White J., Marrack P. C. Self-tolerance eliminates T cells specific for Mls-modified products of the major histocompatibility complex. Nature. 1988 Mar 3;332(6159):35–40. doi: 10.1038/332035a0. [DOI] [PubMed] [Google Scholar]
  30. Kim K. J., Kanellopoulos-Langevin C., Merwin R. M., Sachs D. H., Asofsky R. Establishment and characterization of BALB/c lymphoma lines with B cell properties. J Immunol. 1979 Feb;122(2):549–554. [PubMed] [Google Scholar]
  31. Landolfi N. F., Yin X. M., Capra J. D., Tucker P. W. A conserved heptamer upstream of the IgH promoter region octamer can be the site of a coordinate protein-DNA interaction. Nucleic Acids Res. 1988 Jun 24;16(12):5503–5514. doi: 10.1093/nar/16.12.5503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Laskov R., Scharff M. D. Synthesis, assembly, and secretion of gamma globulin by mouse myeloma cells. I. Adaptation of the Merwin plasma cell tumor-11 to culture, cloning, and characterization of gamma globulin subunits. J Exp Med. 1970 Mar 1;131(3):515–541. doi: 10.1084/jem.131.3.515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lechler R. I., Bal V., Rothbard J. B., Germain R. N., Sekaly R., Long E. O., Lamb J. Structural and functional studies of HLA-DR restricted antigen recognition by human helper T lymphocyte clones by using transfected murine cell lines. J Immunol. 1988 Nov 1;141(9):3003–3009. [PubMed] [Google Scholar]
  34. 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]
  35. Luo Y., Fujii H., Gerster T., Roeder R. G. A novel B cell-derived coactivator potentiates the activation of immunoglobulin promoters by octamer-binding transcription factors. Cell. 1992 Oct 16;71(2):231–241. doi: 10.1016/0092-8674(92)90352-d. [DOI] [PubMed] [Google Scholar]
  36. Luo Y., Roeder R. G. Cloning, functional characterization, and mechanism of action of the B-cell-specific transcriptional coactivator OCA-B. Mol Cell Biol. 1995 Aug;15(8):4115–4124. doi: 10.1128/mcb.15.8.4115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. MacDonald H. R., Schneider R., Lees R. K., Howe R. C., Acha-Orbea H., Festenstein H., Zinkernagel R. M., Hengartner H. T-cell receptor V beta use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature. 1988 Mar 3;332(6159):40–45. doi: 10.1038/332040a0. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Mellins E., Smith L., Arp B., Cotner T., Celis E., Pious D. Defective processing and presentation of exogenous antigens in mutants with normal HLA class II genes. Nature. 1990 Jan 4;343(6253):71–74. doi: 10.1038/343071a0. [DOI] [PubMed] [Google Scholar]
  40. Miller C. L., Garner R., Paetkau V. An activation-dependent, T-lymphocyte-specific transcriptional activator in the mouse mammary tumor virus env gene. Mol Cell Biol. 1992 Jul;12(7):3262–3272. doi: 10.1128/mcb.12.7.3262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Moore R., Dixon M., Smith R., Peters G., Dickson C. Complete nucleotide sequence of a milk-transmitted mouse mammary tumor virus: two frameshift suppression events are required for translation of gag and pol. J Virol. 1987 Feb;61(2):480–490. doi: 10.1128/jvi.61.2.480-490.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Morishima C., Norby-Slycord C., McConnell K. R., Finch R. J., Nelson A. J., Farr A. G., Pullen A. M. Expression of two structurally identical viral superantigens results in thymic elimination at distinct developmental stages. J Immunol. 1994 Dec 1;153(11):5091–5103. [PubMed] [Google Scholar]
  43. Möws C. C., Preiss T., Slater E. P., Cao X., Verrijzer C. P., van Der Vliet P. C., Beato M. Two independent pathways for transcription from the MMTV promoter. J Steroid Biochem Mol Biol. 1994 Oct;51(1-2):21–32. doi: 10.1016/0960-0760(94)90111-2. [DOI] [PubMed] [Google Scholar]
  44. Nakshatri H., Nakshatri P., Currie R. A. Interaction of Oct-1 with TFIIB. Implications for a novel response elicited through the proximal octamer site of the lipoprotein lipase promoter. J Biol Chem. 1995 Aug 18;270(33):19613–19623. doi: 10.1074/jbc.270.33.19613. [DOI] [PubMed] [Google Scholar]
  45. Nicolas J. F., Wegmann D., Lebrun P., Kaiserlian D., Tovey J., Glasebrook A. L. Relationship of B cell Fc receptors to T cell recognition of Mls antigen. Eur J Immunol. 1987 Nov;17(11):1561–1565. doi: 10.1002/eji.1830171106. [DOI] [PubMed] [Google Scholar]
  46. Outram S. V., Owen M. J. The helix-loop-helix containing transcription factor USF activates the promoter of the CD2 gene. J Biol Chem. 1994 Oct 21;269(42):26525–26530. [PubMed] [Google Scholar]
  47. Reimold A. M., Ponath P. D., Li Y. S., Hardy R. R., David C. S., Strominger J. L., Glimcher L. H. Transcription factor B cell lineage-specific activator protein regulates the gene for human X-box binding protein 1. J Exp Med. 1996 Feb 1;183(2):393–401. doi: 10.1084/jem.183.2.393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Reith W., Siegrist C. A., Durand B., Barras E., Mach B. Function of major histocompatibility complex class II promoters requires cooperative binding between factors RFX and NF-Y. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):554–558. doi: 10.1073/pnas.91.2.554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Riley J. L., Westerheide S. D., Price J. A., Brown J. A., Boss J. M. Activation of class II MHC genes requires both the X box region and the class II transactivator (CIITA). Immunity. 1995 May;2(5):533–543. doi: 10.1016/1074-7613(95)90033-0. [DOI] [PubMed] [Google Scholar]
  50. 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]
  51. Ryffel G. U., Kugler W., Wagner U., Kaling M. Liver cell specific gene transcription in vitro: the promoter elements HP1 and TATA box are necessary and sufficient to generate a liver-specific promoter. Nucleic Acids Res. 1989 Feb 11;17(3):939–953. doi: 10.1093/nar/17.3.939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sarkar N. H., Haga S., Lehner A. F., Zhao W., Imai S., Moriwaki K. Insertional mutation of int protooncogenes in the mammary tumors of a new strain of mice derived from the wild in China: normal- and tumor-tissue-specific expression of int-3 transcripts. Virology. 1994 Aug 15;203(1):52–62. doi: 10.1006/viro.1994.1454. [DOI] [PubMed] [Google Scholar]
  53. Seed B., Aruffo A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc Natl Acad Sci U S A. 1987 May;84(10):3365–3369. doi: 10.1073/pnas.84.10.3365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Showe M. K., Williams D. L., Showe L. C. Quantitation of transient gene expression after electroporation. Nucleic Acids Res. 1992 Jun 25;20(12):3153–3157. doi: 10.1093/nar/20.12.3153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Tanaka M., Clouston W. M., Herr W. The Oct-2 glutamine-rich and proline-rich activation domains can synergize with each other or duplicates of themselves to activate transcription. Mol Cell Biol. 1994 Sep;14(9):6046–6055. doi: 10.1128/mcb.14.9.6046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Truss M., Candau R., Chávez S., Beato M. Transcriptional control by steroid hormones: the role of chromatin. Ciba Found Symp. 1995;191:7–23. doi: 10.1002/9780470514757.ch2. [DOI] [PubMed] [Google Scholar]
  57. Tsang S. Y., Nakanishi M., Peterlin B. M. B-cell-specific and interferon-gamma-inducible regulation of the HLA-DR alpha gene. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8598–8602. doi: 10.1073/pnas.85.22.8598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Verrijzer C. P., van Oosterhout J. A., van der Vliet P. C. The Oct-1 POU domain mediates interactions between Oct-1 and other POU proteins. Mol Cell Biol. 1992 Feb;12(2):542–551. doi: 10.1128/mcb.12.2.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Waanders G. A., Lees R. K., Held W., MacDonald H. R. Quantitation of endogenous mouse mammary tumor virus superantigen expression by lymphocyte subsets. Eur J Immunol. 1995 Sep;25(9):2632–2637. doi: 10.1002/eji.1830250934. [DOI] [PubMed] [Google Scholar]
  60. Wen Z., Zhong Z., Darnell J. E., Jr Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995 Jul 28;82(2):241–250. doi: 10.1016/0092-8674(95)90311-9. [DOI] [PubMed] [Google Scholar]
  61. 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]
  62. Winslow G. M., Marrack P., Kappler J. W. Processing and major histocompatibility complex binding of the MTV7 superantigen. Immunity. 1994 Apr;1(1):23–33. doi: 10.1016/1074-7613(94)90006-x. [DOI] [PubMed] [Google Scholar]
  63. 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]
  64. Wright K. L., Moore T. L., Vilen B. J., Brown A. M., Ting J. P. Major histocompatibility complex class II-associated invariant chain gene expression is up-regulated by cooperative interactions of Sp1 and NF-Y. J Biol Chem. 1995 Sep 8;270(36):20978–20986. doi: 10.1074/jbc.270.36.20978. [DOI] [PubMed] [Google Scholar]
  65. Xu L., Haga S., Imai S., Sarkar N. H. Cloning in a plasmid of an MMTV from a wild Chinese mouse: sequencing of the viral LTR. Virus Res. 1994 Aug;33(2):167–178. doi: 10.1016/0168-1702(94)90053-1. [DOI] [PubMed] [Google Scholar]
  66. Xu L., Wrona T. J., Dudley J. P. Exogenous mouse mammary tumor virus (MMTV) infection induces endogenous MMTV sag expression. Virology. 1996 Jan 15;215(2):113–123. doi: 10.1006/viro.1996.0014. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES