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. 1993 Aug;79(4):520–527.

Immunopharmacology of the superantigen staphylococcal enterotoxin A in T-cell receptor V beta 3 transgenic mice.

M Dohlsten 1, M Björklund 1, A Sundstedt 1, G Hedlund 1, D Samson 1, T Kalland 1
PMCID: PMC1421909  PMID: 7691731

Abstract

The response of mouse T cells to the superantigen staphylococcal enterotoxin A (SEA) requires 1000-fold higher concentrations compared to human T cells. In order to develop a sensitive model for SEA studies in mice, the immunopharmacology has been studied in T-cell receptor (TcR) V beta 3 transgenic (TGV beta 3) and non-transgenic (non-TG) C57Bl/6 mice. The frequency of SEA-responsive T cells in the TGV beta 3 mice exceeded 90%, whereas a 10-fold lower frequency was seen in normal C57Bl/6 mice. Nanograms of SEA injected intravenously into TGV beta 3 mice induced strong cytolytic T lymphocyte (CTL) activity against SEA-coated major histocompatibility complex (MHC) class II+ B-lymphoma cells, whereas administration of 1000-fold higher amounts of SEA to non-TG littermates or normal C57Bl/6 mice induced only a moderate response. Kinetic analysis demonstrated that the CTL activity was more rapidly detectable in TG mice, but substantial levels were seen 2 days after SEA injection in both TGV beta 3 and non-TG mice. The cytotoxic T-cell response induced by SEA in TGV beta 3 and non-TG mice was completely MHC class II dependent, as SEA-coated MHC class II-transfected syngeneic B16 melanoma cells but not untransfected B16 cells were sensitive to lysis. Large amounts of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) accumulated in serum of TGV beta 3 mice after injection of 10 ng SEA, whereas only marginal amounts were recorded in non-TG even after injection of 100 micrograms SEA. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated that SEA-induced TNF-alpha and IFN-gamma mRNA reached maximal levels 1 hr after SEA administration in TGV beta 3 mice, whereas peak serum levels of TNF-alpha and IFN-gamma proteins were recorded after 2 hr. Comparison of the mRNA levels of a panel of cytokines in the TGV beta 3 and non-TG mice revealed that almost similar amounts of interleukin-1 (IL-1) were induced in both strains, whereas IL-4 was only detected at significant levels in the TGV beta 3 mouse. The results suggest that TGV beta 3 mice are suitable for studying in vivo immune responses to superantigens at concentrations comparable to the potent effects elicited in humans. Moreover, this model is useful for detailed studies on the dynamic regulation of T-cell activation and anergy induced by superantigens.

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Selected References

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

  1. Andersson U., Adolf G., Dohlsten M., Möller G., Sjögren H. O. Characterization of individual tumor necrosis factor alpha-and beta-producing cells after polyclonal T cell activation. J Immunol Methods. 1989 Oct 24;123(2):233–240. doi: 10.1016/0022-1759(89)90227-5. [DOI] [PubMed] [Google Scholar]
  2. Beisel W. R. Pathophysiology of staphylococcal enterotoxin, type B, (SEB) toxemia after intravenous administration to monkeys. Toxicon. 1972 Aug;10(5):433–440. doi: 10.1016/0041-0101(72)90167-5. [DOI] [PubMed] [Google Scholar]
  3. Berg L. J., Pullen A. M., Fazekas de St Groth B., Mathis D., Benoist C., Davis M. M. Antigen/MHC-specific T cells are preferentially exported from the thymus in the presence of their MHC ligand. Cell. 1989 Sep 22;58(6):1035–1046. doi: 10.1016/0092-8674(89)90502-3. [DOI] [PubMed] [Google Scholar]
  4. Brenner C. A., Tam A. W., Nelson P. A., Engleman E. G., Suzuki N., Fry K. E., Larrick J. W. Message amplification phenotyping (MAPPing): a technique to simultaneously measure multiple mRNAs from small numbers of cells. Biotechniques. 1989 Nov-Dec;7(10):1096–1103. [PubMed] [Google Scholar]
  5. Callahan J. E., Herman A., Kappler J. W., Marrack P. Stimulation of B10.BR T cells with superantigenic staphylococcal toxins. J Immunol. 1990 Apr 1;144(7):2473–2479. [PubMed] [Google Scholar]
  6. Carlsson R., Fischer H., Sjögren H. O. Binding of staphylococcal enterotoxin A to accessory cells is a requirement for its ability to activate human T cells. J Immunol. 1988 Apr 15;140(8):2484–2488. [PubMed] [Google Scholar]
  7. Cherwinski H. M., Schumacher J. H., Brown K. D., Mosmann T. R. Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med. 1987 Nov 1;166(5):1229–1244. doi: 10.1084/jem.166.5.1229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. 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]
  10. 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]
  11. Dohlsten M., Hedlund G., Akerblom E., Lando P. A., Kalland T. Monoclonal antibody-targeted superantigens: a different class of anti-tumor agents. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9287–9291. doi: 10.1073/pnas.88.20.9287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Ferran C., Sheehan K., Dy M., Schreiber R., Merite S., Landais P., Noel L. H., Grau G., Bluestone J., Bach J. F. Cytokine-related syndrome following injection of anti-CD3 monoclonal antibody: further evidence for transient in vivo T cell activation. Eur J Immunol. 1990 Mar;20(3):509–515. doi: 10.1002/eji.1830200308. [DOI] [PubMed] [Google Scholar]
  13. Fischer H., Dohlsten M., Andersson U., Hedlund G., Ericsson P., Hansson J., Sjögren H. O. Production of TNF-alpha and TNF-beta by staphylococcal enterotoxin A activated human T cells. J Immunol. 1990 Jun 15;144(12):4663–4669. [PubMed] [Google Scholar]
  14. Fischer H., Dohlsten M., Lindvall M., Sjögren H. O., Carlsson R. Binding of staphylococcal enterotoxin A to HLA-DR on B cell lines. J Immunol. 1989 May 1;142(9):3151–3157. [PubMed] [Google Scholar]
  15. Fraser J. D. High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature. 1989 May 18;339(6221):221–223. doi: 10.1038/339221a0. [DOI] [PubMed] [Google Scholar]
  16. Gascoigne N. R., Ames K. T. Direct binding of secreted T-cell receptor beta chain to superantigen associated with class II major histocompatibility complex protein. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):613–616. doi: 10.1073/pnas.88.2.613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gjörloff A., Fischer H., Hedlund G., Hansson J., Kenney J. S., Allison A. C., Sjögren H. O., Dohlsten M. Induction of interleukin-1 in human monocytes by the superantigen staphylococcal enterotoxin A requires the participation of T cells. Cell Immunol. 1991 Oct 1;137(1):61–71. doi: 10.1016/0008-8749(91)90056-h. [DOI] [PubMed] [Google Scholar]
  18. Gjörloff A., Hedlund G., Kalland T., Sansom D., Fischer H., Trowsdale J., Sjögren H. O., Dohlsten M. The LFA-3 adhesion pathway is differently utilized by superantigen-activated human CD4+ T-cell subsets. Scand J Immunol. 1992 Aug;36(2):243–250. doi: 10.1111/j.1365-3083.1992.tb03096.x. [DOI] [PubMed] [Google Scholar]
  19. Hedlund G., Dohlsten M., Herrmann T., Buell G., Lando P. A., Segrén S., Schrimsher J., MacDonald H. R., Sjögren H. O., Kalland T. A recombinant C-terminal fragment of staphylococcal enterotoxin A binds to human MHC class II products but does not activate T cells. J Immunol. 1991 Dec 15;147(12):4082–4085. [PubMed] [Google Scholar]
  20. Hedlund G., Dohlsten M., Petersson C., Kalland T. Superantigen-based tumor therapy: in vivo activation of cytotoxic T cells. Cancer Immunol Immunother. 1993;36(2):89–93. doi: 10.1007/BF01754407. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Herman A., Labrecque N., Thibodeau J., Marrack P., Kappler J. W., Sekaly R. P. Identification of the staphylococcal enterotoxin A superantigen binding site in the beta 1 domain of the human histocompatibility antigen HLA-DR. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):9954–9958. doi: 10.1073/pnas.88.22.9954. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Herrmann T., Baschieri S., Lees R. K., MacDonald H. R. In vivo responses of CD4+ and CD8+ cells to bacterial superantigens. Eur J Immunol. 1992 Jul;22(7):1935–1938. doi: 10.1002/eji.1830220739. [DOI] [PubMed] [Google Scholar]
  23. Hodoval L. F., Morris E. L., Crawley G. J., Beisel W. R. Pathogenesis of lethal shock after intravenous staphylococcal enterotoxin B in monkeys. Appl Microbiol. 1968 Feb;16(2):187–192. doi: 10.21236/ad0666852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Höidén I., Möller G. Interferon-gamma and growth factor production by murine T cells derived from three different lymphoid tissues. Eur J Immunol. 1991 Nov;21(11):2703–2709. doi: 10.1002/eji.1830211109. [DOI] [PubMed] [Google Scholar]
  25. Janeway C. A., Jr Selective elements for the V beta region of the T cell receptor: Mls and the bacterial toxic mitogens. Adv Immunol. 1991;50:1–53. doi: 10.1016/s0065-2776(08)60821-4. [DOI] [PubMed] [Google Scholar]
  26. Jett M., Brinkley W., Neill R., Gemski P., Hunt R. Staphylococcus aureus enterotoxin B challenge of monkeys: correlation of plasma levels of arachidonic acid cascade products with occurrence of illness. Infect Immun. 1990 Nov;58(11):3494–3499. doi: 10.1128/iai.58.11.3494-3499.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Jett M., Brinkley W., Neill R., Gemski P., Hunt R. Staphylococcus aureus enterotoxin B challenge of monkeys: correlation of plasma levels of arachidonic acid cascade products with occurrence of illness. Infect Immun. 1990 Nov;58(11):3494–3499. doi: 10.1128/iai.58.11.3494-3499.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Johnson H. M., Magazine H. I. Potent mitogenic activity of staphylococcal enterotoxin A requires induction of interleukin 2. Int Arch Allergy Appl Immunol. 1988;87(1):87–90. doi: 10.1159/000234654. [DOI] [PubMed] [Google Scholar]
  29. Kawabe Y., Ochi A. Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J Exp Med. 1990 Oct 1;172(4):1065–1070. doi: 10.1084/jem.172.4.1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Komisar J., Rivera J., Vega A., Tseng J. Effects of staphylococcal enterotoxin B on rodent mast cells. Infect Immun. 1992 Jul;60(7):2969–2975. doi: 10.1128/iai.60.7.2969-2975.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. MacDonald H. R., Baschieri S., Lees R. K. Clonal expansion precedes anergy and death of V beta 8+ peripheral T cells responding to staphylococcal enterotoxin B in vivo. Eur J Immunol. 1991 Aug;21(8):1963–1966. doi: 10.1002/eji.1830210827. [DOI] [PubMed] [Google Scholar]
  32. Marrack P., Blackman M., Kushnir E., Kappler J. The toxicity of staphylococcal enterotoxin B in mice is mediated by T cells. J Exp Med. 1990 Feb 1;171(2):455–464. doi: 10.1084/jem.171.2.455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. Newell K. A., Ellenhorn J. D., Bruce D. S., Bluestone J. A. In vivo T-cell activation by staphylococcal enterotoxin B prevents outgrowth of a malignant tumor. Proc Natl Acad Sci U S A. 1991 Feb 1;88(3):1074–1078. doi: 10.1073/pnas.88.3.1074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Olson R. D., Stevens D. L., Melish M. E. Direct effects of purified staphylococcal toxic shock syndrome toxin 1 on myocardial function of isolated rabbit atria. Rev Infect Dis. 1989 Jan-Feb;11 (Suppl 1):S313–S315. doi: 10.1093/clinids/11.supplement_1.s313. [DOI] [PubMed] [Google Scholar]
  36. Pontzer C. H., Irwin M. J., Gascoigne N. R., Johnson H. M. T-cell antigen receptor binding sites for the microbial superantigen staphylococcal enterotoxin A. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7727–7731. doi: 10.1073/pnas.89.16.7727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Powers G. D., Abbas A. K., Miller R. A. Frequencies of IL-2- and IL-4-secreting T cells in naive and antigen-stimulated lymphocyte populations. J Immunol. 1988 May 15;140(10):3352–3357. [PubMed] [Google Scholar]
  38. Raj H. D., Bergdoll M. S. Effect of enterotoxin B on human volunteers. J Bacteriol. 1969 May;98(2):833–834. doi: 10.1128/jb.98.2.833-834.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Rellahan B. L., Jones L. A., Kruisbeek A. M., Fry A. M., Matis L. A. In vivo induction of anergy in peripheral V beta 8+ T cells by staphylococcal enterotoxin B. J Exp Med. 1990 Oct 1;172(4):1091–1100. doi: 10.1084/jem.172.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Rott O., Wekerle H., Fleischer B. Protection from experimental allergic encephalomyelitis by application of a bacterial superantigen. Int Immunol. 1992 Mar;4(3):347–353. doi: 10.1093/intimm/4.3.347. [DOI] [PubMed] [Google Scholar]
  41. Russell J. K., Pontzer C. H., Johnson H. M. Both alpha-helices along the major histocompatibility complex binding cleft are required for staphylococcal enterotoxin A function. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7228–7232. doi: 10.1073/pnas.88.16.7228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Scholl P. R., Trede N., Chatila T. A., Geha R. S. Role of protein tyrosine phosphorylation in monokine induction by the staphylococcal superantigen toxic shock syndrome toxin-1. J Immunol. 1992 Apr 1;148(7):2237–2241. [PubMed] [Google Scholar]
  43. Smith H. P., Le P., Woodland D. L., Blackman M. A. T cell receptor alpha-chain influences reactivity to Mls-1 in V beta 8.1 transgenic mice. J Immunol. 1992 Aug 1;149(3):887–896. [PubMed] [Google Scholar]
  44. Swain S. L., McKenzie D. T., Weinberg A. D., Hancock W. Characterization of T helper 1 and 2 cell subsets in normal mice. Helper T cells responsible for IL-4 and IL-5 production are present as precursors that require priming before they develop into lymphokine-secreting cells. J Immunol. 1988 Nov 15;141(10):3445–3455. [PubMed] [Google Scholar]
  45. Taub D. D., Newcomb J. R., Rogers T. J. Effect of isotypic and allotypic variations of MHC class II molecules on staphylococcal enterotoxin presentation to murine T cells. Cell Immunol. 1992 May;141(2):263–278. doi: 10.1016/0008-8749(92)90147-h. [DOI] [PubMed] [Google Scholar]
  46. Vacchio M. S., Kanagawa O., Tomonari K., Hodes R. J. Influence of T cell receptor V alpha expression on Mlsa superantigen-specific T cell responses. J Exp Med. 1992 May 1;175(5):1405–1408. doi: 10.1084/jem.175.5.1405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. 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]
  48. Yagi J., Baron J., Buxser S., Janeway C. A., Jr Bacterial proteins that mediate the association of a defined subset of T cell receptor:CD4 complexes with class II MHC. J Immunol. 1990 Feb 1;144(3):892–901. [PubMed] [Google Scholar]
  49. Yamamoto J. K., Farrar W. L., Johnson H. M. Interleukin 2 regulation of mitogen induction of immune interferon (IFN gamma) in spleen cells and thymocytes. Cell Immunol. 1982 Jan 15;66(2):333–341. doi: 10.1016/0008-8749(82)90183-6. [DOI] [PubMed] [Google Scholar]

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