Cancer Immunology, Immunotherapy

, Volume 33, Issue 4, pp 231–237 | Cite as

Bacterial superantigens as anti-tumour agents: induction of tumour cytotoxicity in human lymphocytes by staphylococcal enterotoxin A

  • Peter A. Lando
  • Gunnar Hedlund
  • Mikael Dohlsten
  • Terje Kalland
Original articles


Activation of lymphocytes by interleukin-2 (IL-2) induces lymphokine-activated killer (LAK) cells that show promising effects on tumour growth in clinical trials. We examined the effect of the superantigen staphylococcal enterotoxin A (SEA) on anti-tumour activity of freshly prepared human lymphocytes. Picomolar amounts of SEA rapidly induced cytotoxic activity against K562 and Raji cells as well as some natural-killer(NK)-resistant tumour cell lines. Cytotoxic activity was not dependent on target cell expression of either major histocompatibility complex (MHC) class I or II antigens as shown using mutated cell lines. Cell-sorting experiments showed that the activity was expressed by NK (CD5CD56+) as well as T (CD5+) cells, although the former contained the majority of cytotoxic activity. NK cells could not be directly activated by SEA. In contrast, SEA activated purified T cells to the same extent as in bulk cultures. It is suggested that SEA activation of NK cells is secondary to that brought about by lymphokines produced by T cells. Activation of LAK cells with SEA was comparable in magnitude as well as target cell spectrum to that of IL-2. In addition to the LAK-like cytotoxic activity induced by SEA, a superimposed cytotoxicity towards target cells expressing MHC class II antigens coated with SEA was observed. This staphylococcal-enterotoxin-dependent cell-mediated cytotoxicity (SDCC) was exclusively mediated by T cells. It is well established that MHC class II antigens function as receptors for staphylococcal enterotoxins on mammalian cells and that the complex between MHC class II antigen and — SEA apparently functions as a target structure for activated T cells with target cell lysis as a consequence. Activation of T lymphocytes with IL-2 also resulted in the capability to mediate SDCC. Staphylococcal enterotoxins represent a novel way of inducing anti-tumour activity in human lymphocytes, which could be of value in therapeutic applications.

Key words

Bacterial superantigens Antitumor agents Enterotoxin A Lymphocytes 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Acolla RJ (1983) Human B cell variants immunoselected against a single Ia antigen subset have lost expression of several subsets. J Exp Med 157: 1053PubMedGoogle Scholar
  2. 2.
    Andersson U, Adolf G, Dohlsten M, Möller G, Sjögren H-O (1989) Characterisation of individual tumour necrosis factor alpha- and beta-producing cells after polyclonal T cell activation. J Immunol Methods 123: 233PubMedGoogle Scholar
  3. 3.
    Bankhurst AD, Imir T (1989) The mechanisms involved in the activation of human natural killer cells by staphylococcal enterotoxin B. Cell Immunol 122: 108PubMedGoogle Scholar
  4. 4.
    Buell G, Schulz M-F, Selzer G, Chollet A, Movva NR, Semon D, Escanez S, Kawashima E (1985) Optimising the expression inE. coli of a synthetic gene encoding somatomedin-C (IGF-I). Nucleic Acids Res 13: 1923PubMedGoogle Scholar
  5. 5.
    Carlsson R, Sjögren H-O (1985) Kinetics of IL-2 and interferongamma production, expression of IL-2 receptors, and cell proliferation in human mononuclear cells exposed to staphylococcal enterotoxin A. Cell Immunol 96: 175PubMedGoogle Scholar
  6. 6.
    Dohlsten M, Sjögren H-O, Carlsson R (1986) Histamine inhibits interferon-gamma production via suppression of interleukin 2 synthesis. Cell Immunol 101: 493PubMedGoogle Scholar
  7. 7.
    Dohlsten M, Hedlund G, Sjögren H-O, Carlsson R (1988) Two subsets of human CD4+ T helper cells differing in kinetics and capacities to produce interleukin-2 and interferon-gamma can be defined by the Leu-18 and UCHL1 monoclonal antibodies. Eur J Immunol 18: 1173PubMedGoogle Scholar
  8. 8.
    Dohlsten M, Lando PA, Hedlund G, Trowsdale J, Kalland T (1990) Targeting of human cytotoxic T lymphocytes to MHC class II expressing cells by staphylococcal enterotoxins. Immunology 71: 96PubMedGoogle Scholar
  9. 9.
    Ellis TM, McKenzie RS, Simms PE, Helfrich BA, Fischer RI (1989) Induction of human lymphokine-activated killer cells by IFN-alfa and IFN-gamma. J Immunol 143: 4282PubMedGoogle Scholar
  10. 10.
    Fischer H, Dohlsten M, Lindvall M, Sjögren H-O, Carlsson R (1989) Binding of staphylococcal enterotoxin A to HLA-DR on B cell lines. J Immunol 142: 3151PubMedGoogle Scholar
  11. 11.
    Fischer H, Dohlsten M, Andersson U, Hedlund G, Ericsson P, Hansson J, Sjögren H-O (1990) Production of TNF-alpha and TNF-beta by staphylococcal enterotoxin A activated human T cells. J Immunol 144: 4663PubMedGoogle Scholar
  12. 12.
    Fraser JD (1989) High-affinity binding of staphylococcal enterotoxins A and B to HLA-DR. Nature 339: 221PubMedGoogle Scholar
  13. 13.
    Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumour cells by interleukin 2 activated autologous human peripheral blood lymphocytes. J Exp Med 155: 1823PubMedGoogle Scholar
  14. 14.
    Hedlund G, Dohlsten M, Lando P, Kalland T (1990) Staphylococcal enterotoxins direct and trigger CTL-killing of autologous HLA-DR+ mononuclear leukocytes and freshly prepared leukemia cells. Cell Immunol 129: 426PubMedGoogle Scholar
  15. 15.
    Henkart P, Martz E (eds) (1985) Mechanism of cell mediated cytotoxicity. Plenum, New York, p1Google Scholar
  16. 16.
    Higuchi CM, Thompson JA, Lindgren CG, Gills S, Widmer MB, Kern DE, Fefer A (1989) Induction of lymphokine-activated killer activity by interleukin 4 in human lymphocytes preactivated by interleukin 2 in vivo or in vitro. Cancer Res 49: 6487PubMedGoogle Scholar
  17. 17.
    Jung G, Martin DE, Muller-Eberhard HJ (1987) Induction of cytotoxicity in human peripheral blood mononuclear cells by monoclonal antibody OKT3. J Immunol 139: 639PubMedGoogle Scholar
  18. 18.
    Kalland T, Belfrage H, Bhiladvala P, Hedlund G (1987) Analysis of the murine lymphokine-activated killer (LAK) cell phenomenon: dissection of effectors and progenitors into NK- and T-like cells. J Immunol 138: 3640PubMedGoogle Scholar
  19. 19.
    Kappler J, Kotzin B, Herron L, Gelfand EW, Bigler RD, Boylston A, Carrel S, Posnett DN, Yongwon C, Marrack P (1989) Vβ-specific stimulation of human T cells by staphylococcal Toxins. Science 244: 811PubMedGoogle Scholar
  20. 20.
    Kawakami Y, Custer MC, Rosenberg SA, Lotze MT (1989) IL-4 regulates IL-2 induction of lymphokine-activated killer activity from human lymphocytes. J Immunol 142: 3452PubMedGoogle Scholar
  21. 21.
    Kotasek D, Vercellotti GM, Ochoa AC, Bach FH, Jacob HS (1987) Lymphokine activated killer (LAK) cell-mediated endothelial injury: a mechanism for capillary leak syndrome in patients treated with LAK cells and interleukin-2. Trans Assoc Am Physicians 100: 21PubMedGoogle Scholar
  22. 22.
    Lando P, Dohlsten M, Kalland T, Sjögren H-O, Carlsson R (1990) The TcR-CD3 complex is required for activation of human lymphocytes with staphylococcal enterotoxin A. Scand J Immunol 31: 133PubMedGoogle Scholar
  23. 23.
    Marrack P, Kappler J (1990). The staphylococcal enterotoxins and their relatives. Science 248: 705PubMedGoogle Scholar
  24. 24.
    Mazumder A, Grimm EA, Rosenberg SA (1983) Characterisation of the lysis of fresh human solid tumours by autologous lymphocytes activated in vitro with phytohemagglutinin. J Immunol 130: 958PubMedGoogle Scholar
  25. 25.
    Mortarini R, Belli F, Parmiani G, Anichini A (1990) Cytokine-mediated modulation of HLA-Class II, ICAM-1, LFA-3 and tumour associated antigen profile of melanoma cells. Comparison with antiproliferative activity by rIL-1-beta, rTNF-alpha, rIFN-gamma, rIL-4 and their combinations. Int J Cancer 45: 334PubMedGoogle Scholar
  26. 26.
    Ochoa AC, Hasz DE, Rezonzew R, Anderson PM, Bach FH (1989) Lymphokine-activated killer activity in long-term cultures with anti-CD3 plus interleukin. 2: identification and isolation of effector subsets. Cancer Res 49: 963PubMedGoogle Scholar
  27. 27.
    Perlmann P, Cerottini JC (1979) Cytotoxic lymphocytes. In: Sela V (ed) The antigens. Academic Press, New York, p 173Google Scholar
  28. 28.
    Platsoucas CD, Oleszak EL, Good RA (1986) Immunomodulation of human leukocytes by staphylococcal enterotoxin A: augmentation of natural killer cells and induction of suppressor cells. Cell Immunol 97: 371PubMedGoogle Scholar
  29. 29.
    Rabinowich H, Cohen R, Bruderman I, Steiner Z, Klajman A (1987) Functional analysis of mononuclear cells infiltrating into tumours: lysis of autologous human tumour cells by cultured infiltrating lymphocytes. Cancer Res 47: 173PubMedGoogle Scholar
  30. 30.
    Rodewald HR, Koszinowski UH, Eichmann K, Melchers I (1989) Predominant utilisation of Vβ+ T cell receptor genes in the H-2Ld-restricted cytotoxic T cell response against the immediate-early protein pp89 of the murine cytomegalovirus. J Immunol 143: 4238PubMedGoogle Scholar
  31. 31.
    Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertsson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE (1987) A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin 2 or high-dose interleukin 2 alone. N Engl J Med 361: 889Google Scholar
  32. 32.
    Rust JJC, Verreck F, Vietor H, Koning F (1990) Specific recognition of staphylococcal enterotoxin A by human T cells bearing receptors with the Vγ region. Nature 346: 572PubMedGoogle Scholar
  33. 33.
    Silvennoinen O, Vakkila J, Hurme M (1988) Accessory cells, dendritic cells, or monocytes, are required for the lymphokine-activated killer cell induction from resting T cell but not from natural killer cell precursors. J Immunol 141: 1404PubMedGoogle Scholar
  34. 34.
    Tilden AB, Itoh K, Balch CM (1987) Human lymphokine-activated killer (LAK) cells: identification of two types of effector cells. J Immunol 138: 1068PubMedGoogle Scholar
  35. 35.
    Tomai M, Kotb M, Majumudar G, Beachley EH (1990) Superantigenicity of streptococcal M protein. J Exp Med 172: 359PubMedGoogle Scholar
  36. 36.
    Topalian SL, Solomon D, Rosenberg SA (1989) Tumour-specific cytolysis by lymphocytes infiltrating human melanomas. J Immunol 142: 3714PubMedGoogle Scholar
  37. 37.
    Valentin H, Groux H, Gelin C, Chretien I, Bernard A (1990) Modulation of lymphokine release and cytolytic activities by activating peripheral blood lymphocytes via CD2. J Immunol 144: 875PubMedGoogle Scholar
  38. 38.
    White J, Herman A, Pullen AM, Kubo R, Kappler JW, and Marrack P (1989) The Vβ-specific superantigen staphylococcal enterotoxin B: Stimulation of mature T cells and clonal deletion in neonatal mice. Cell 56: 27PubMedGoogle Scholar
  39. 39.
    Zamvil SS, Mitchell DJ, Lee NE, Moore AC, Waldor MK, Sakai K, Rothbard JB, McDevitt SS, Steinman L, Acha-Orbea H (1988) Predominant expression of a T cell receptor gene family in autoimmune encephalomyelitis. J Exp Med 167: 1586PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Peter A. Lando
    • 1
  • Gunnar Hedlund
    • 1
    • 2
  • Mikael Dohlsten
    • 1
    • 2
  • Terje Kalland
    • 1
    • 2
  1. 1.Kabi Pharmacia Therapeutics ABLundSweden
  2. 2.The Department of Tumour Immunology, The Wallenberg LaboratoryUniversity of LundLundSweden

Personalised recommendations