Shedding of Interleukin-2 Receptor in Cutaneous Lymphomas: An Effective Mechanism to Circumvent Immunosurveillance?

  • Reinhard Dummer
  • Frank Nestle
  • Gerhard Posseckert
  • Jurgen C. Becker
  • Günter Burg
Part of the NATO ASI Series book series (NSSA, volume 265)


Serum levels of soluble interleukin-2 receptor (sIL-2R) were determined by an ELISA technique and cytotoxic activity of peripheral mononuclear cells (PMC) measured by a four hour 51Cr release assay in patients with cutaneous T cell lymphoma (CTCL). In addition, the clinical course of these patients was followed. A significant negative correlation between serum sIL-2R and NK-activity was found (p < 0.05, n = 19). Both parameters seem to be prognostic factors for disease progression. After a four day IL-2 stimulation, the increase in cytotoxicity of CTCL PMC resembled the increase observed in control PMC. In CTCL serum, however, IL-2 dependent augmentation of cytotoxicity was reduced. IL-2 affinity chromatography of serum from one CTCL patient produced an enrichment of sIL-2R which was able to inhibit IL-2 effects.

Western blotting characterized this IL-2 inhibitor as multimeric TAC-protein (sIL-2R α-chain).

Transfection of NIH 3T3 fibroblasts resulted in production of a recombinant TAC-protein present in monomelic (45 kDa) and dimeric (90 kDa) forms.

In vitro studies revealed a dose-dependent inhibition of IL-2 induced lymphokine-activated killer cell activity and of phytohemagglutinin (PHA) blast proliferation by recombinant sIL-2R.

Our data demonstrate that sIL-2R is capable of inhibiting IL-2 dependent cell proliferation and induction of cytotoxicity. We conclude that the negative correlation between sIL-2R and NK-activity in CTCL patients may be caused by neutralization of IL-2 by sIL-2R. This could be an important mechanism for escape from immunosurveillance in lymphoma patients.


Natural Killer Cell Activity Mycosis Fungoides Natural Killer Activity Inflammatory Skin Disease Peripheral Mononuclear Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alexander P, 1974. Escape from immune destruction by the host through shedding of surface antigens: Is this a characteristic shared by malignant and embryonic cells? Cancer Res., 34: 2077–2082.PubMedGoogle Scholar
  2. Becker JC, R Dummer, G Burg and RE Schmidt, 1991. Shedding of ICAM-1 from human melanoma cell lines induced by IFN-gamma and TNF-alpha: Functional consequences on cell mediated cytotoxicity. J. Immunol., 147: 4398–4401.PubMedGoogle Scholar
  3. Blitterswijk WJ van, P Emmelot, HA Hilkmann, J Hilgers and CA Feltkamp, 1979. Rigid plasma-membrane derived vesicles, enriched in tumour-associated surface antigens (MLr) occuring in the ascites fluid of a murine leukemia (GRSL). Int. J. Cancer, 23: 62–70.PubMedCrossRefGoogle Scholar
  4. Bunn PA and SI Lamberg, 1979. Report of the committee on staging and classification of cutaneous T-cell lymphomas. Cancer Treat Rep., 63: 725–728. In: G Burg, O Braun-Falco, Eds: Cutaneous Lymphomas, Pseudolymphome and Related Disorders. Springer, Berlin, Heidelberg, New York, Tokyo, 1983.PubMedGoogle Scholar
  5. Burg G, R Dummer, M Wilhelm, F Nestle, MM Ott, A Feller, H Hefner, U Lanz, A Schwinn and J Wiede, 1991. Primary subcutaneous (“lipotropic”) lymphoma of T-cell receptor delta-positive, interferon-gamma producing T-cells. N. Engl. J. Med. 325: 1078–1081.PubMedCrossRefGoogle Scholar
  6. Dummer R, F Nestle, J Wiede, E Schafer, J Roger, JC Becker, T Vogt and G Burg, 1991. Coincidence of increased interleukin-2 receptors, diminished natural killer cell activity and progressive disease in cutaneous T-cell lymphomas. Eur. J. Dermatol. 1: 135–138.Google Scholar
  7. Dummer R, G Posseckert, F Nestle, M Burger, R Witzgall, JC Becker, E Schafer, J Wiede, W Sebald and G Burg, 1992. Soluble interleukin-2 receptors inhibit interleukin-2 dependent proliferation and cytotoxicity: Explanation for diminished NK activity in cutaneous lymphomas in vivo? J. Invest, Dermatol., 98: 50–54.CrossRefGoogle Scholar
  8. Engelmann H, D Novick and D Wallach, 1990. Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J, Biol. Chem., 265: 1531–1536.Google Scholar
  9. Fanslow WC, JE Sims, H Sassenfeld, PJ Morrissey, S Gillis, SK Dower and MB Widmer, 1990. Regulation of alloreactivity in vivo by a soluble form of the interleukin-1 receptor. Science, 248: 739–742.PubMedCrossRefGoogle Scholar
  10. Fujimoto J, S Levy and R Levy, 1983. Spontaneous release of the Leu-2 (T8) molecule from human T cells. J. Exp. Med., 159: 752–766.CrossRefGoogle Scholar
  11. Gilmore SJ, EM Benson and JWI Kelly, 1991. T-cell subsets with a naive phenotype are selectively decreased in the peripheral blood of patients with mycosis fungoides. J. Invest. Dermatol., 96: 50–56.PubMedCrossRefGoogle Scholar
  12. Gatanga T, C Hwang, W Kohr, F Cappuccini, JA Lucci, EWB Jeffes, R Lentz, J Tomich, RS Yamamoto and GA Granger, 1990. Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients. Proc. Natl. Acad. Sci. USA, 87: 8781–8784.CrossRefGoogle Scholar
  13. Gause A, V Roschansky, A Tschiersch, R Schmits, V Diehl and M Pfreundschuh, 1990. The prognostic value of low pretreatment serum interleukin-2 receptor (sIL-2R) in patients with Hodgkin’s disease (HD). J. Cancer Res. Clin. Oncol., 116: 320.SGoogle Scholar
  14. Honda M, K Kitamura, T Takeshita, K Sugamura and T Tokunaga, 1990. Identification of a soluble IL-2 receptor β-chain from human lymphoid cell line cells. J. Immunol., 145: 4131–4135.PubMedGoogle Scholar
  15. Kantor AF, EC Rochelle, EC Vonderheid, EJ Van Scott and JFF Fraumeni, 1989. Risk of second malignancy after cutaneous T-cell lymphoma. Cancer, 63: 1612–1615.PubMedCrossRefGoogle Scholar
  16. Kapp A, A Piskorski and E Schop, 1988. Elevated levels of interleukin-2 receptors in sera with atopic dermatitis and psoriasis. Br. J. Dermatol., 119: 707–710.PubMedCrossRefGoogle Scholar
  17. Karasuyama H and F Melchers F, 1988. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4, 5 using modified cDNA expression vectors. Eur. J. Immunol., 18: 97–104.PubMedCrossRefGoogle Scholar
  18. Kaudewitz P, O Josimovic-Alasevic, T Diamantstein, F Eckert, K Klepzig and G Burg, 1988. Soluble IL-2 receptor serum levels in cutaneous T-cell lymphoma: Correlation with clinical stage and IL-2 receptor status in cutaneous infiltrates. J. Invest. Dermatol., 91: 386–387.Google Scholar
  19. Kaye FJ, PA Bunn, SM Steinberg, DC lhde, AB Fischmann, EJ Glatstein, GP Schechter, RM Phelbs, FM Foss, HL Parlette, MJ Anderson and EA Sausville, 1989. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N. Engl. J. Med., 321: 1784–1790.PubMedCrossRefGoogle Scholar
  20. Kerl K and W Sterry, 1987. Classification and staging. In: G Burg, W Sterry, Eds: EORTC/BMFT Cutaneous Lymphoma Project Group: Recommendations for staging and therapy of cutaneous lymphomas. EORTC, Brussels, pp 1–10.Google Scholar
  21. Laroche L and D Kaiserlian, 1983. Decreased natural killer cell activity in cutaneous T-cell lymphomas. New Engl. J. Med., 306: 101–102.Google Scholar
  22. Leonard WJ, JM Depper, M Kanehisa, M Krönke, NJ Peffer, PB Svetlik, M Sullivan and WC Greene, 1985. Structure of the human interleukin-2 receptor gene. Science, 230: 633–639.PubMedCrossRefGoogle Scholar
  23. Levy S, JL Tempe, P Caussade, A Aleksijevic, E Grosshans, S Mayer and JM Lang, 1984. Stage related decrease in natural killer cell activity in untreated patients with mycosis fungoides. Cancer Immunol. Immunother., 18: 138–140.PubMedCrossRefGoogle Scholar
  24. Miedel MC, JD Hulmes, DV Weber, P Bailon and YCE Pan, 1988. Structural analysis of recombinant soluble human interleukin 2 receptor. Biochem. Biophys. Res. Commun., 54: 372–379.CrossRefGoogle Scholar
  25. Moreland AA, DB Robertson and LT Heffner, 1985. Treatment of cutaneous T-cell lymphoma with cyclosporin A. J. Am. Acad. Dermatol., 12: 886–887.PubMedCrossRefGoogle Scholar
  26. Mosley B, MP Beckmann, CJ March, RL Idzerda, SD Gimpel, T VandenBos, D Friend, A Alpert, D Anderson, J Jackson, JM Wignall, C Smith, B Gallis, JE Sims, D Urdal, MB Widmer, D Cosman and LS Park, 1989. The murine interleukin-4 receptor: Molecular cloning and characterization of secreted and membrane bound forms. Cell 59: 335–348.PubMedCrossRefGoogle Scholar
  27. Nikaido T, A Shimizu, N Ishida, H Sabe, K Teshigawara, M Maeda, T Uchiyama, J Yodoi and T Honjo, 1984. Molecular cloning of cDNA encoding human IL-2 receptor. Nature, 311: 631–635.PubMedCrossRefGoogle Scholar
  28. Raz A, R Goldmann, I Yuli and M Inbar, 1978. Isolation of plasma membrane fragments and vesicules from ascites fluids of lymphoma bearing mice and their possible role in the escape mechanism of tumours from host immune rejection. Cancer Immunol. Immunother., 4: 53–59.CrossRefGoogle Scholar
  29. Robb RJ, A Munck and KA Smith, 1981. T cell growth factor receptors: Quantification, specifity and biological relevance. J. Exp. Med., 154: 1455–1472.PubMedCrossRefGoogle Scholar
  30. Rubin LA, G Jay and DI Nelson, 1986. The released interleukin-2 receptor binds interleukin-2 efficiently. J. Immunol., 137: 3841–3844.PubMedGoogle Scholar
  31. Rubin LA, CC Kurman, ME Fritz, WE Biddison, R Boutin, R Yarchoan and DL Nelson, 1985. Soluble interleukin-2 receptors are released from activated human lymphoid cells in vitro. J. Immunol., 135: 3172–3177.PubMedGoogle Scholar
  32. Rusk CM, MP Neeper, L-M Kuo, RM Kutny and RJ Robb, 1988. Structure-activity analysis of modified and truncated forms of the TAC receptor protein: Site specific mutagenesis of cysteine residues. J. Immunol., 140: 2249–2259.PubMedGoogle Scholar
  33. Sanders ME, MW Makgoba and S Shaw, 1988. Human naive and memory cells: Reinterpretion of helper-inducer and suppressor-inducer subsets. Immunol. Today, 9: 195–198.PubMedCrossRefGoogle Scholar
  34. Shapiro PE, D Warburton, CL Berger and RL Edelson, 1987. Clonal chromosomal abnormalities in cutaneous T-cell lymphoma. Cancer Genet Cytogenet, 28: 267–276.PubMedCrossRefGoogle Scholar
  35. Smart JE, PC Familletti, DV Weber, RF Keeney and P Bailon, 1990. Purification of the IL-2 receptor (TAC) by ligand-affinity chromatography and utilization of the immobilized receptor for receptor-affinity chromatography (RAC) purification of IL-2, mutant IL-2, and IL-2 fusion proteins. J. Invest. Dermatol., 94: 158–163.CrossRefGoogle Scholar
  36. Smith CA, T Davis, JM Wignall, WS Din, T Farrah, C Upton, G McFadden and RG Goodwin, 1991. T2 open reading frame from the Shope fibroma virus encodes a soluble form of the TNF receptor. Biochem. Biophys. Res, Commun., 176: 335–342.CrossRefGoogle Scholar
  37. Sterry W and V Mielke, 1989. CD 4+ cutaneous T-cell lymphomas show the phenotype of helper/inducer T cells. J. Invest. Dermatol., 93: 413–416.PubMedCrossRefGoogle Scholar
  38. Symons JA, NC Wood, FS DiGiovine and GW Duff, 1988. Soluble IL-2 receptor in rheumatoid arthritis: Correlation with disease activity, IL-1 and IL-2 inhibition. J. Immunol., 141: 2612–2618.PubMedGoogle Scholar
  39. Symons JA, JF McCulloch, NC Wood and GW Duff, 1991. Soluble CD4 in patients with rheumatoid arthritis and osteoarthritis. Clin. Immunol. Immunopathol., 60: 72–82.PubMedCrossRefGoogle Scholar
  40. Thomsen X and GL Wantzin, 1987. Extracutaneous spreading with fatal outcome of mycosis fungoides in a patient treated with cyclosporin A: A word of caution. Dermatologica, 174: 236–238.PubMedCrossRefGoogle Scholar
  41. Tron VA, DR Rosenthal and DN Sauder, 1988. Epidermal interleukin-1 is increased in cutaneous T-cell lymphoma. J. Invest. Dermatol., 90: 378–381.PubMedCrossRefGoogle Scholar
  42. Wagner DK, J Kiwanuka, BK Edwards, LA Rubin, DL Nelson and IT Magrath, 1987. Soluble interleukin-2 receptor levels in patients with undifferentiated and lymphoblastic lymphomas: Correlation with survival. J. Clin. Oncol., 5: 1262–1274.PubMedGoogle Scholar
  43. Weber DV, RF Keeney, PC Familletti and P Bailon, 1988. Medium scale ligand-affinity purification of two soluble forms of human IL-2 receptor. J. Chromatogr., 431: 55–63.PubMedCrossRefGoogle Scholar
  44. Weber W, G Gill and J Spiess, 1984. Production of an epidermal growth factor receptor-related protein. Science, 224: 294–297.PubMedCrossRefGoogle Scholar
  45. Weigel U, M Meyer and W Sebald, 1989. Mutant proteins of human interleukin-2. Eur. J. Biochem., 180: 295–300.PubMedCrossRefGoogle Scholar
  46. Yamada S, FW Ruscetti, WA Overton, RB Herbermann, MC Birchenall Sparks and JR Ortaldo, 1987. Regulation of human large granular lymphocyte and T cell growth by recombinant interleukin 2: Induction of interleukin 2 receptor and promotion of growth of cells with enhanced cytotoxicity. J. Leuk. Biol., 41: 505–517.Google Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Reinhard Dummer
    • 1
  • Frank Nestle
    • 1
  • Gerhard Posseckert
    • 2
  • Jurgen C. Becker
    • 3
  • Günter Burg
    • 1
  1. 1.Department of DermatologyUniversity of ZurichZurichSwitzerland
  2. 2.Department of BiochemistryUniversity of WürzburgWürzburgGermany
  3. 3.Department of DermatologyUniversity of WürzburgWürzburgGermany

Personalised recommendations