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Interleukin-2-induced lymphoproliferative responses

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Summary

Interleukin-2 (IL-2) is capable of both stimulating an in vitro lymphoproliferative response and augmenting non-major-histocompatibility-complex-(MHC)-restricted cytotoxicity. However, there are conflicting reports about the phenotypes of responding cells. In the present studies, we determined phenotypes of Ficoll/Hypaque-separated peripheral blood mononuclear cells stimulated with 50, 100 or 1000 U/ml IL-2; analyses were performed after 1, 3 and 5 weeks. With all concentrations, there was a progressive increase in CD3+ cells; after 3–5 weeks more than 90% of the cells reacted with this antibody. However, the proportions of CD4+ and CD8+ cells proved to be a function of the IL-2 concentration. Cultures containing 50 U/ml or 100 U/ml favored the expansion of the CD4+ subset. By contrast, in cultures stimulated with 1000 U/ml, CD8+ cells predominated. At baseline, CD8+ cells comprised 28±2%; after 3 weeks, this value increased to 51±5%. In addition, the proportion of CD56+ (Leu19, NKH-1) cells depended on the amount of IL-2. At 50 U/ml, there was no appreciable change in CD56+ cells. However, at 1000 U/ml, CD56+ cells increased from 17±1% (day 0) to 39±4% (3 weeks). This increase was primarily due to an expansion of the CD3+ CD56+ subset (non-NMC restricted cytotoxic T cells). By contrast, natural killer (NK) cells, as measured by the CD16 antibody, steadily declined at all IL-2 concentrations.

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References

  1. Braakman E, Van Tunen A, Meager A, Lucas CJ (1986) IL-2- and IFNγ-enhanced natural cytotoxic activity: analysis of the role of different lymphoid subsets and implications for activation routes. Cell Immunol 99: 476

    Google Scholar 

  2. Byrne JA, Butler JL, Cooper MD (1988) Differential activation requirements for virgin and memory T cells. J Immunol 141: 3249

    Google Scholar 

  3. Damle NK, Doyle LV, Bradley EC (1986) Interleukin 2-activated human killer cells are derived from phenotypically heterogeneous precursors. J Immunol 137: 2814

    Google Scholar 

  4. Ferrini S, Miescher S, Zocchi MR, Von Fliedner V, Moretta A (1987) Phenotypic and functional characterization of recombinant interleukin 2 (rIL-2)-induced activated killer cells: analysis at the population and clonal levels. J Immunol 138: 1297

    Google Scholar 

  5. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine-activated killer cell phenomenon. J Exp Med 155: 1823

    Google Scholar 

  6. Grimm EA, Ramsey KM, Mazumder A, Wilson DJ, Djeu JY, Rosenberg SA (1983) Lymphokine-activated killer cell phenomenon. II. Precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus-derived lymphocytes, and natural killer cells. J Exp Med 157: 884

    Google Scholar 

  7. Gullberg M, Smith KA (1986) Regulation of T cell autocrine growth. T4+ cells become refractory to interleukin 2. J Exp Med 163: 270

    Google Scholar 

  8. Harel-Bellan A, Bertoglio J, Quillet A, Marchiol C, Wakasugi H, Mishall Z, Fradelizi D (1986) Interleukin 2 (IL 2) up-regulates its own receptor on a subset of human unprimed peripheral blood lymphocytes and triggers their proliferation. J Immunol 136: 2463

    Google Scholar 

  9. Herberman RB (1987) Lymphokine-activated killer cell activity. Immunol Today 8: 178

    Google Scholar 

  10. Holter W, Majdic O, Liszka K, Stockinger H, Knapp W (1985) Kinetics of activation antigen expression by in vitro-stimulated human T lymphocytes. Cell Immunol 90: 322

    Google Scholar 

  11. Itoh K, Tilden AB, Kumagai K, Balch CM (1985) Leu-11+ lymphocytes with natural killer (NK) activity are precursors of recombinant interleukin 2 (rIL 2)-induced activated killer (AK) cells. J Immunol 134: 802

    Google Scholar 

  12. Kabelitz D, Kirchner H, Armerding D, Wagner H (1985) Recombinant interleukin 2 rapidly augments human natural killer cell activity. Cell Immunol 93: 38

    Google Scholar 

  13. Kanar MC, Winkelstein A, Platt D (1983) Naturally occurring cell-medicated cytotoxicity against SV40 3T3 murine tumor cells. J Natl Cancer Inst 70: 267

    Google Scholar 

  14. Kronke M, Leonard WJ, Depper JM, Greene WC (1985) Sequential expression of genes involved in human T lymphocyte growth and differentiation. J Exp Med 161: 1593

    Google Scholar 

  15. Lanier LL, Le AM, Ding A, Evans EL, Krensky AM, Clayberger C, Phillips JH (1983) Expression of Leu 19 (NKH-1) antigen on IL-2 dependent cytotoxic and non cytotoxic T cell lines. J Immunol 138: 2019

    Google Scholar 

  16. Lanier LL, Le AM, Phillips JH, Warner NL, Babcock GF (1983) Subpopulations of human natural killer cells defined by expression of the Leu-7 (HNK-1) and Leu-11 (NK-15) antigens. J Immunol 131: 1789

    Google Scholar 

  17. Lanier LL, Benike CJ, Phillips JH, Engleman EG (1985) Recombinant interleukin 2 enhanced natural killer cell-mediated cytotoxicity in human lymphocyte subpopulations expressing the Leu 7 and Leu 11 antigens. J Immunol 134: 794

    Google Scholar 

  18. Lanier LL, Le AM, Civin CI, Loken MR, Phillips JH (1986) The relationship of CD16 (Leu-11) and Leu-19 (NHK-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes. J Immunol 136: 4480

    Google Scholar 

  19. Lanier LL, Le AM, Cwirla S, Federspiel N, Phillips JH (1986) Antigenic, functional, and molecular genetic studies of human natural killer cells and cytotoxic T lymphocytes not restricted by the major histocompatibility complex. Fed Proc 45: 2823

    Google Scholar 

  20. Malek TR, Ashwell JD (1985) Interleukin 2 upregulates expression of its receptor on a T cell clone. J Exp Med 161: 1575

    Google Scholar 

  21. Michon JM, Caligiuri MA, Hazanow SM, Levine H, Schlossman SF, Ritz J (1988) Induction of natural killer effectors from human thymus with recombinant IL-2. J Immunol 140: 3660

    Google Scholar 

  22. Mookerjee BK, Pauly JL (1985) Human recombinant interleukin-2 is mitogenic to human lymphocytes. J Leukocyte Biol 38: 553

    Google Scholar 

  23. Morimoto C, Letvin NL, Distaso JA, Aldrich WR, Schlossman SF (1985) The isolation and characterization of the human suppressor inducer T cell subset. J Immunol 134: 1508

    Google Scholar 

  24. Morimoto C, Letvin NL, Boyd AW, Hagan M, Brown HM, Kornacki MM, Schlossman SF (1985) The isolation and characterization of human helper inducer T cell subset. J Immunol 134: 3762

    Google Scholar 

  25. Ortaldo JR, Mason A, Overton R (1986) Lymphokine-activated killer cells: analysis of progenitors and effectors. J Exp Med 164: 1193

    Google Scholar 

  26. Phillips JH, Lanier LL (1986) Dissection of the lymphokine-activated killer phenomenon. Relative contribution of peripheral blood natural killer cells and T lymphocytes to cytolysis. J Exp Med 164: 814

    Google Scholar 

  27. Ramsdell FJ, Shau H, Golub SH (1988) Role of proliferation in LAK cell development. Cancer Immunol Immunother 26: 139

    Google Scholar 

  28. Roosnek EE, Brouwer MC, Kipp JB, Aarden LA (1986) Monocytedependent induction of proliferation of human peripheral T cells by recombinant interleukin 2. Eur J Immunol 16: 35

    Google Scholar 

  29. Rosenberg SA, Lotze MT (1986) Cancer immunotherapy using interleukin-2 and interleukin-2-activated lymphocytes. Annu Rev Immunol 4: 681

    Google Scholar 

  30. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Simpson C, Reichert CM (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313: 1485

    Google Scholar 

  31. Sanders ME, Makgoba MW, Shaw S (1988) Human naive and memory T cells. Immunol Today 9: 195

    Google Scholar 

  32. Sawada H, Abo T, Sugawara S, Kumagai K (1988) Prerequisite for the induction of lymphokine-activated killer cells from T lymphocytes. J Immunol 140: 3668

    Google Scholar 

  33. Smith KA, Cantrell DA (1985) Interleukin 2 regulates its own receptors. Proc Natl Acad Sci USA 82: 864

    Google Scholar 

  34. Talmadge JE, Wiltrout RH, Counts DF, Herberman RB, McDonald T, Ortaldo JR (1986) Proliferation of human peripheral blood lymphocytes induced by recombinant human interleukin 2: contribution of large granular lymphocytes and T lymphocytes. Cell Immunol 102: 261

    Google Scholar 

  35. Taylor DS, Kern JA, Nowell PC (1986) IL-2 alone is mitogenic only for TAC-positive lymphocytes in human peripheral blood. J Immunol 136: 1620

    Google Scholar 

  36. Tilden AB, Itoh K, Balch CM (1987) Human lymphokine-activated killer (LAK) cells: identification of two types of effector cells. J Immunol 138: 1068

    Google Scholar 

  37. Toribio ML, DeLandazuri MO, Lopez-Botet M (1983) Induction of natural killer-like cytotoxicity in cultured human thymocytes. Eur J Immunol 13: 964

    Google Scholar 

  38. Trinchieri G, Matsumoto-Kobayashi M, Clark SC, Seehra J, London L, Perussia B (1984) Response of resting human peripheral blood natural killer cells to interleukin 2. J Exp Med 160: 1147

    Google Scholar 

  39. Umiel T, Saltz-Tal E (1986) Phenotypic analysis of activation antigens on mitogen-stimulated T cells utilizing monoclonal antibodies. In: Reinherz EL, Haynes BF, Nadler LM, Berstein ID (eds) Leukocyte typing: II, vol 1. Springer-Verlag, New York, pp 441–451

    Google Scholar 

  40. Welte K, Andreeff M, Platzer E, Holloway K, Rubin BY, Moore MAS, Mertelsmann R (1984) Interleukin 2 regulates the expression of TAC antigen on peripheral blood T lymphocytes. J Exp Med 160: 1390

    Google Scholar 

  41. White WB, Ballow M (1985) Modulation of suppressor-cell activity by cimetidine in patients with common variable hypogammaglobulinemia. N Engl J Med 312: 198

    Google Scholar 

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Authors and Affiliations

  1. Department of Medicine Montefiore Hospital, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, 15 213, Pittsburgh, Pa., USA

    Alan Winkelstein, Leslie D. Weaver, Nan Salva & Laurie L. Machen

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  1. Alan Winkelstein
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  2. Leslie D. Weaver
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  3. Nan Salva
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  4. Laurie L. Machen
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These studies were supported by a grant from the National Cancer Institute, NIH (RO1 CA24429-15)

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Winkelstein, A., Weaver, L.D., Salva, N. et al. Interleukin-2-induced lymphoproliferative responses. Cancer Immunol Immunother 32, 110–116 (1990). https://doi.org/10.1007/BF01754207

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  • DOI: https://doi.org/10.1007/BF01754207

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