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. 1995 Nov 1;182(5):1493–1504. doi: 10.1084/jem.182.5.1493

The use of mammary tumor virus (Mtv)-negative and single-Mtv mice to evaluate the effects of endogenous viral superantigens on the T cell repertoire

PMCID: PMC2192179  PMID: 7595219

Abstract

Most laboratory strains of mice have between two and eight endogenous superantigens. These viral superantigens (vSAGs) are coded by genes in the 3' long terminal repeats of endogenous mammary tumor viruses (Mtv's). A line of Mtv-negative mice and several lines of mice containing single Mtv's were created by inbreeding the F2 progeny of CBA/CaJ and C58/J mice, which have no Mtv integrants in common. This allowed the T cell repertoire of H-2k mice, unaffected by Mtv superantigens, as well as the effects of vSAGs upon that repertoire, to be studied. Although each individual mouse had a different mix of C58/J and CBA/CaJ background genes, the T cell repertoires of different Mtv- negative mice were very similar and were reproducible. Since the background genes did not affect the V beta repertoire, there are no super-antigens, other than those encoded by Mtv's, that differ between CBA/CaJ and C58/J. CD4 and CD8 T cells had quite different repertoires in the Mtv-negative mice because of the effects of class I and class II major histocompatibility complex molecules on positive and negative selection. vSAG3 was found to delete V beta 5 T cells, while vSAG8 deleted V beta 7 T cells, and vSAG9 deleted V beta 13 T cells in addition to their previously reported specificities. vSAG17 deletes a small proportion of CD4+ T cells bearing V beta 11 and -12. vSAG14 and - 30 have little effect on the T cell repertoire and are not expressed in thymocytes and splenocytes. An endogenous superantigen that has a low avidity for a particular V beta may positively select thymocytes, leading to an increased frequency of peripheral T cells bearing the relevant V beta s. We found evidence that vSAG11 may positively select T cells bearing V beta 8.2. Our data, which analyzed the effects of seven endogenous Mtv's, showed little evidence of positive selection by any other vSAGs on T cells bearing any V beta tested, despite published reports to the contrary.

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Selected References

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  1. 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]
  2. Ashton-Rickardt P. G., Bandeira A., Delaney J. R., Van Kaer L., Pircher H. P., Zinkernagel R. M., Tonegawa S. Evidence for a differential avidity model of T cell selection in the thymus. Cell. 1994 Feb 25;76(4):651–663. doi: 10.1016/0092-8674(94)90505-3. [DOI] [PubMed] [Google Scholar]
  3. Benoist C., Mathis D. Positive selection of the T cell repertoire: where and when does it occur? Cell. 1989 Sep 22;58(6):1027–1033. doi: 10.1016/0092-8674(89)90501-1. [DOI] [PubMed] [Google Scholar]
  4. Bevan M. J. In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells. Nature. 1977 Sep 29;269(5627):417–418. doi: 10.1038/269417a0. [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., Palmer E. Positive selection of CD4+ T cells mediated by MHC class II-bearing stromal cell in the thymic cortex. Nature. 1989 Oct 19;341(6243):649–651. doi: 10.1038/341649a0. [DOI] [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. Cohen J. C., Traina V. L., Breznik T., Gardner M. Development of a mouse mammary tumor virus-negative mouse strain: a new system for the study of mammary carcinogenesis. J Virol. 1982 Dec;44(3):882–885. doi: 10.1128/jvi.44.3.882-885.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Foo-Phillips M., Kozak C. A., Principato M. A., Abe R. Characterization of the Mlsf system. II. Identification of mouse mammary tumor virus proviruses involved in the clonal deletion of self-Mlsf-reactive T cells. J Immunol. 1992 Dec 1;149(11):3440–3447. [PubMed] [Google Scholar]
  12. 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]
  13. Gallahan D., Callahan R. Mammary tumorigenesis in feral mice: identification of a new int locus in mouse mammary tumor virus (Czech II)-induced mammary tumors. J Virol. 1987 Jan;61(1):66–74. doi: 10.1128/jvi.61.1.66-74.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gollob K. J., Palmer E. Divergent viral superantigens delete V beta 5+ T lymphocytes. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):5138–5141. doi: 10.1073/pnas.89.11.5138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Haskins K., Hannum C., White J., Roehm N., Kubo R., Kappler J., Marrack P. The antigen-specific, major histocompatibility complex-restricted receptor on T cells. VI. An antibody to a receptor allotype. J Exp Med. 1984 Aug 1;160(2):452–471. doi: 10.1084/jem.160.2.452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hogquist K. A., Jameson S. C., Heath W. R., Howard J. L., Bevan M. J., Carbone F. R. T cell receptor antagonist peptides induce positive selection. Cell. 1994 Jan 14;76(1):17–27. doi: 10.1016/0092-8674(94)90169-4. [DOI] [PubMed] [Google Scholar]
  18. Hugo P., Kappler J. W., Marrack P. C. Positive selection of TcR alpha beta thymocytes: is cortical thymic epithelium an obligatory participant in the presentation of major histocompatibility complex protein? Immunol Rev. 1993 Oct;135:133–155. doi: 10.1111/j.1600-065x.1993.tb00647.x. [DOI] [PubMed] [Google Scholar]
  19. Ignatowicz L., Kappler J. W., Marrack P., Scherer M. T. Identification of two V beta 7-specific viral superantigens. J Immunol. 1994 Jan 1;152(1):65–71. [PubMed] [Google Scholar]
  20. Janeway C. A., Jr Are there cellular superantigens? Immunol Rev. 1993 Feb;131:189–200. doi: 10.1111/j.1600-065x.1993.tb01536.x. [DOI] [PubMed] [Google Scholar]
  21. Jouvin-Marche E., Marche P. N., Six A., Liebe-Gris C., Voegtle D., Cazenave P. A. Identification of an endogenous mammary tumor virus involved in the clonal deletion of V beta 2 T cells. Eur J Immunol. 1993 Nov;23(11):2758–2764. doi: 10.1002/eji.1830231106. [DOI] [PubMed] [Google Scholar]
  22. Kanagawa O., Palmer E., Bill J. The T cell receptor V beta 6 domain imparts reactivity to the Mls-1a antigen. Cell Immunol. 1989 Apr 1;119(2):412–426. doi: 10.1016/0008-8749(89)90255-4. [DOI] [PubMed] [Google Scholar]
  23. Kang J. J., Schwegel T., Knepper J. E. Sequence similarity between the long terminal repeat coding regions of mammary-tumorigenic BALB/cV and renal-tumorigenic C3H-K strains of mouse mammary tumor virus. Virology. 1993 Sep;196(1):303–308. doi: 10.1006/viro.1993.1480. [DOI] [PubMed] [Google Scholar]
  24. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Kisielow P., Blüthmann H., Staerz U. D., Steinmetz M., von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature. 1988 Jun 23;333(6175):742–746. doi: 10.1038/333742a0. [DOI] [PubMed] [Google Scholar]
  27. Korman A. J., Bourgarel P., Meo T., Rieckhof G. E. The mouse mammary tumour virus long terminal repeat encodes a type II transmembrane glycoprotein. EMBO J. 1992 May;11(5):1901–1905. doi: 10.1002/j.1460-2075.1992.tb05242.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kubo R. T., Born W., Kappler J. W., Marrack P., Pigeon M. Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors. J Immunol. 1989 Apr 15;142(8):2736–2742. [PubMed] [Google Scholar]
  29. Kuo W. L., Vilander L. R., Huang M., Peterson D. O. A transcriptionally defective long terminal repeat within an endogenous copy of mouse mammary tumor virus proviral DNA. J Virol. 1988 Jul;62(7):2394–2402. doi: 10.1128/jvi.62.7.2394-2402.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lee B. K., Eicher E. M. Segregation patterns of endogenous mouse mammary tumor viruses in five recombinant inbred strain sets. J Virol. 1990 Sep;64(9):4568–4572. doi: 10.1128/jvi.64.9.4568-4572.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. Lo D., Ron Y., Sprent J. Induction of MHC-restricted specificity and tolerance in the thymus. Immunol Res. 1986;5(3):221–232. doi: 10.1007/BF02919203. [DOI] [PubMed] [Google Scholar]
  34. Lo D., Sprent J. Identity of cells that imprint H-2-restricted T-cell specificity in the thymus. Nature. 1986 Feb 20;319(6055):672–675. doi: 10.1038/319672a0. [DOI] [PubMed] [Google Scholar]
  35. Luther S., Shakhov A. N., Xenarios I., Haga S., Imai S., Acha-Orbea H. New infectious mammary tumor virus superantigen with V beta-specificity identical to staphylococcal enterotoxin B (SEB). Eur J Immunol. 1994 Aug;24(8):1757–1764. doi: 10.1002/eji.1830240806. [DOI] [PubMed] [Google Scholar]
  36. 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]
  37. 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]
  38. Murphy K. M., Heimberger A. B., Loh D. Y. Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. Science. 1990 Dec 21;250(4988):1720–1723. doi: 10.1126/science.2125367. [DOI] [PubMed] [Google Scholar]
  39. Necker A., Rebaï N., Matthes M., Jouvin-Marche E., Cazenave P. A., Swarnworawong P., Palmer E., MacDonald H. R., Malissen B. Monoclonal antibodies raised against engineered soluble mouse T cell receptors and specific for V alpha 8-, V beta 2- or V beta 10-bearing T cells. Eur J Immunol. 1991 Dec;21(12):3035–3040. doi: 10.1002/eji.1830211220. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Pullen A. M., Marrack P., Kappler J. W. The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens. Nature. 1988 Oct 27;335(6193):796–801. doi: 10.1038/335796a0. [DOI] [PubMed] [Google Scholar]
  42. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Scherer M. T., Ignatowicz L., Winslow G. M., Kappler J. W., Marrack P. Superantigens: bacterial and viral proteins that manipulate the immune system. Annu Rev Cell Biol. 1993;9:101–128. doi: 10.1146/annurev.cb.09.110193.000533. [DOI] [PubMed] [Google Scholar]
  44. Sebzda E., Wallace V. A., Mayer J., Yeung R. S., Mak T. W., Ohashi P. S. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science. 1994 Mar 18;263(5153):1615–1618. doi: 10.1126/science.8128249. [DOI] [PubMed] [Google Scholar]
  45. Sha W. C., Nelson C. A., Newberry R. D., Kranz D. M., Russell J. H., Loh D. Y. Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature. 1988 Nov 3;336(6194):73–76. doi: 10.1038/336073a0. [DOI] [PubMed] [Google Scholar]
  46. Shakhov A. N., Wang H., Acha-Orbea H., Pauley R. J., Wei W. Z. A new infectious mammary tumor virus in the milk of mice implanted with C4 hyperplastic alveolar nodules. Eur J Immunol. 1993 Nov;23(11):2765–2769. doi: 10.1002/eji.1830231107. [DOI] [PubMed] [Google Scholar]
  47. Tomonari K., Fairchild S. Positive and negative selection of Tcrb-V6+ T cells. Immunogenetics. 1992;36(4):230–237. doi: 10.1007/BF00215053. [DOI] [PubMed] [Google Scholar]
  48. Tomonari K., Fairchild S. Positive selection of Tcrb-V4+CD8+ T cells by H-2d molecules. Immunogenetics. 1990;32(4):290–292. doi: 10.1007/BF00187101. [DOI] [PubMed] [Google Scholar]
  49. Tomonari K., Fairchild S., Rosenwasser O. A. Influence of viral superantigens on V beta- and V alpha-specific positive and negative selection. Immunol Rev. 1993 Feb;131:131–168. doi: 10.1111/j.1600-065x.1993.tb01534.x. [DOI] [PubMed] [Google Scholar]
  50. Tomonari K., Hederer R., Hengartner H. Positive selection of Tcrb-V10b+ T cells. Immunogenetics. 1992;35(1):9–15. doi: 10.1007/BF00216621. [DOI] [PubMed] [Google Scholar]
  51. Utsunomiya Y., Bill J., Palmer E., Gollob K., Takagaki Y., Kanagawa O. Analysis of a monoclonal rat antibody directed to the alpha-chain variable region (V alpha 3) of the mouse T cell antigen receptor. J Immunol. 1989 Oct 15;143(8):2602–2608. [PubMed] [Google Scholar]
  52. 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]
  53. Waanders G. A., McDonald H. R. Hierarchy of responsiveness in vivo and in vitro among T cells expressing distinct Mls-1a-reactive v beta domains. Eur J Immunol. 1992 Jan;22(1):291–293. doi: 10.1002/eji.1830220144. [DOI] [PubMed] [Google Scholar]
  54. Woodland D. L., Smith H. P., Surman S., Le P., Wen R., Blackman M. A. Major histocompatibility complex-specific recognition of Mls-1 is mediated by multiple elements of the T cell receptor. J Exp Med. 1993 Feb 1;177(2):433–442. doi: 10.1084/jem.177.2.433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. 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]
  56. Yazdanbakhsh K., Park C. G., Winslow G. M., Choi Y. Direct evidence for the role of COOH terminus of mouse mammary tumor virus superantigen in determining T cell receptor V beta specificity. J Exp Med. 1993 Aug 1;178(2):737–741. doi: 10.1084/jem.178.2.737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Yoon S. T., Dianzani U., Bottomly K., Janeway C. A., Jr Both high and low avidity antibodies to the T cell receptor can have agonist or antagonist activity. Immunity. 1994 Oct;1(7):563–569. doi: 10.1016/1074-7613(94)90046-9. [DOI] [PubMed] [Google Scholar]
  58. Zinkernagel R. M., Callahan G. N., Althage A., Cooper S., Klein P. A., Klein J. On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? J Exp Med. 1978 Mar 1;147(3):882–896. doi: 10.1084/jem.147.3.882. [DOI] [PMC free article] [PubMed] [Google Scholar]

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