Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1994 Aug;85(8):853–861. doi: 10.1111/j.1349-7006.1994.tb02958.x

Induction Mechanism of Human Blood CD8+ T Cell Proliferation and Cytotoxicity by Natural Killer Cell Stimulatory Factor (Interleukin‐12)

Roustem Nabioullin 1,✉, Saburo Sone 1, Akihiko Nil 1, Takashi Haku 1, Takeshi Ogura 1
PMCID: PMC5919563  PMID: 7928632

Abstract

Natural killer cell stimulatory factor (NKSFJ IL‐12) has been found to induce cytotoxic activity of human blood T cells. In the present study, the effect of NKSF on induction of cytotoxic CD8+ T cells in the presence or absence of monocytes was examined. Highly purified lymphocytes (>99%) and monocytes (>90%) were isolated hy centrifugal elutriation from peripheral blood of normal donors. Then, CD8+ cells were isolated with antibody‐bound magnetic beads from purified lymphocytes. The cytotoxicity of CD8+ cells was measured by 51Cr release assay for 4 h. NKSF enhanced the proliferative response of CD8+ cells stimulated with suboptimal concentrations of interleukin‐2 (IL‐2), but rather inhibited their proliferative and cytotoxic responses on stimulation with an optimal concentration of IL‐2. NKSF stimulated CD8+ cells to produce interferon 7 (IFNγ) irrespective of the presence of added IL‐2, and this effect was augmented by co‐cultivation with monocytes. Blood monocytes upregulated induction of cytotoxic CD8+ cells stimulated with NKSF alone, and this effect was abolished by addition of antibody against IFNγ, but not of antibody against tumor necrosis factor a. Induction of NKSF‐inducible cytotoxic CD8+ cells was inhibited by addition of transforming growth factor β, but not of IL‐4. These observations suggest that in situ induction of NKSF‐stimulated cytotoxic CD8+ cells may be regulated by complex cytokine networks, depending on the participation of monocytes.

Keywords: CD8+ cell, Monocyte, IL‐12, Natural killer cell stimulatory factor, IFN

Full Text

The Full Text of this article is available as a PDF (502.8 KB).

REFERENCES

  • 1. ) Young , J. D.Killing of target cells by lymphocytes: mechanistic view . PhysioL Rev. , 69 , 250 – 314 ( 1989. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Podack , E. R.Molecular mechanism of lymphocyte‐mediated tumor cell lysis . Immunol. Today , 6 , 21 – 27 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Kern , D. E. , Gillis , S. , Okada , M. and Henney , C. S.The role of interleukin‐2 (IL‐2) in the differentiation of cytotoxic T cells: the effect of monoclonal antibody and absorption with IL‐2 dependent T cell lines. J . Immunol. , 127 , 1323 – 1328 ( 1981. ). [PubMed] [Google Scholar]
  • 4. ) Spits , H. , Yssel , H. , Paliard , ‐X. , Kastelein , R. , Figdor , C. and de Vries , J. E.IL‐4 inhibits IL‐2‐mediated induction of human lymphokine‐activated killer cells, but not the generation of antigen‐specific cytotoxic T lymphocytes in mixed leukocyte cultures . J. Immunol. , 141 , 29 – 36 ( 1988. ). [PubMed] [Google Scholar]
  • 5. ) Takai , Y. , Wong , G. , Clarke , S. C. , Burakiff , S. J. and Herrmann , S.B cell stimulatory factor‐2 is involved in the differentiation of cytotoxic T lymphocytes . J. Immunol. , 140 , 508 – 512 ( 1988. ). [PubMed] [Google Scholar]
  • 6. ) Alderson , M. R. , Sassenfeld , H. M. and Widmer , M. B.Interleukin 7 enhances cytolytic T lymphocyte generation and induces lymphekine‐activated killer cells from human peripheral blood . J. Exp. Med. , 172 , 577 – 587 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Ochoa , A. , Gromo , G. , Barbara , B. J. , Sondel , P. M. and Bach , F. H.Long term growth of lymphokine‐activated killer (LAK) cells: role of anti‐CD3, β‐IL‐1, interferon‐γ and ‐β. J . Immunol. , 138 , 2728 – 2733 ( 1978. ). [PubMed] [Google Scholar]
  • 8. ) Owen‐Schaub , L. B. , Gutterman , J. U. and Grimm , E. A.A synergy of tumor necrosis factor and interleukin‐2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor‐α and interleukin‐2 in the generation of human lymphokine‐activated killer cell cytotoxicity . Cancer Res. , 48 , 788 – 792 ( 1988. ). [PubMed] [Google Scholar]
  • 9. ) Sone , S. , Yanagawa , H. , Nii , A. and Ogura , T.Induction of interleukin 2‐activated killer effector activity and its regulatory mechanism . Gann Monogr. Cancer Res. , 40 , 81 – 93 ( 1993. ). [Google Scholar]
  • 10. ) Kobayashi , M. , Fitz , L. , Ryan , M. , Hewick , R. M. , Clark , S. C. , Chan , S. , Loudon , R. , Sherman , F. , Perussia , B. and Trinchieri , G.Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes . J. Exp. Med. , 170 , 827 – 845 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. ) Chan , S. H. , Perussia , B. , Gupta , J. W. , Kobayashi , M. , Pospisil , M. , Young , H. A. , Wolf , S. F. , Young , D. , Clark , S. C. and Trinchieri , G.Induction of interferon γ production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers . J. Exp. Med. , 173 , 869 – 879 ( 1991. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. ) Chehimi , J. , Starr , S. E. , Frank , I. , Rengaraju , M. , Jackson , S. J. , Llanes , C. , Kobayashi , M. , Perussia , B. , Young , D. , Nickbarg , E. , Wolf , S. F. and Trinchieri , G.Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus‐infected patients . J. Exp. Med , 175 , 789 – 796 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) Robertson , M. J. , Soiffer , R. J. , Wolf , S. F. , Manley , T. J. , Donahue , C. , Young , D. , Hermann , S. H. and Ritz , J.Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity and proliferation of NK cells are differently regulated by NKSF . J Exp. Med. , 175 , 779 – 788 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Chan , S. H. , Kobayashi , M. , Santoli , D. , Perussia , B. and Trinchieri , G.Mechanisms of IFN‐γ induction by natural killer cell stimulatory factor (NKSF/IL‐12). Role of transcription and mRNA stability in the synergistic interaction between NKSF and IL‐2 . J, Immunol. , 148 , 92 – 98 ( 1992. ). [PubMed] [Google Scholar]
  • 15. ) Gately , M. K. , Wilson , D. E. and Wong , H. L.Synergism between recombinant interleukin 2 (IL‐2) and IL‐2‐depleted lymphokine containing supernatants in facilitating allogeneic human cytolytic T lymphocyte responses in vitro . J. Immunol. , 135 , 1274 – 1281 ( 1986. ). [PubMed] [Google Scholar]
  • 16. ) Gately , M. K. , Desai , B. B. , Woltizky , A. G. , Quinn , P. M. , Dwyer , C. M. , Podlaski , F. J. , Familletti , P. C. , Sinigaglia , F. , Chizonnite , R. , Gubler , U. and Stern , A. S.Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL‐12 (cytotoxic lymphocyte maturation factor) . J. Immunol. , 147 , 874 – 882 ( 1991. ). [PubMed] [Google Scholar]
  • 17. ) Kato , K. , Yamada , T. , Kawahara , K. , Onda , H. , Asano , T. , Sugino , H. and Kakimura , A.Purification and characterization of recombinant human interleukin‐2 produced in Escherichia coli Biochem . Biophys. Res. Commun. , 130 , 692 – 699 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Sone , S. , Yanagawa , H. , Nishioka , Y. , Orino , E. , Bhaskaran , G. , Nii , A. , Mizuno , K. , Heike , Y. , Ogushi , F. and Ogura , T.Interleukin‐4 as a potent down‐regulator for human alveolar macrophages capable of producing tumor necrosis factor‐a and interleukin‐1 . Eur. Respir. J. , 5 , 174 – 181 ( 1992. ). [PubMed] [Google Scholar]
  • 19. ) Orino , E. , Sone , S. , Nii , A. and Ogura , T.IL‐4 up‐regulate IL‐1 receptor antagonist gene expression and its production in human blood monocytes . J. Immunol , 149 , 925 – 931 ( 1992. ). [PubMed] [Google Scholar]
  • 20. ) Sugihara , K. , Sone , S. , Shono , M. , Nii , A. , Munekata , M. , Okumura , K. and Ogura , T.Enhancement by monocytes of perforin production and its gene expression by human CD8+ T cells stimulated with interleukin‐2 . Jpn. J. Cancer Res. , 83 , 1223 – 1230 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Sone , S. , Utsugi , T. , Nii , A. and Ogura , T.Effect of human alveolar macrophages on the induction of lymphokine (IL‐2)‐activated killer cells . J. Immunol. , 139 , 29 – 34 ( 1987. ). [PubMed] [Google Scholar]
  • 22. ) Hart , P. H. , Fitti , G. F. , Burgess , D. R. , Whitty , G. A. , Piccoli , D. S. and Hamilton , J. A.Potential antiinflam‐matory effects of interleukin 4: suppression of human monocyte tumor necrosis factor a, interleukin 1, and pros‐taglandin E2 , Proc. Natl. Acad. Sci. USA , 86 , 3803 – 3807 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. ) Nishioka , Y. , Sone , S. , Orino , E. , Nii , A. and Ogura , T.Down‐regulation by interleukin 4 of activation of human alveolar macrophages to the tumoricidal state . Cancer Res. , 51 , 5526 – 5531 ( 1991. ). [PubMed] [Google Scholar]
  • 24. ) Chantry , D. , Turner , M. , Abney , E. and Feldman , M.Modulation of cytokine production by transforming growth factor‐bL . J. Immunol , 142 , 4295 – 4300 ( 1989. ). [PubMed] [Google Scholar]
  • 25. ) D'Andrea , A. , Rengaraju , M. , Valiante , N. M. , Chehimi , J. , Kubin , M. , Aste , M. , Chan , S. H. , Kobayashi , M. , Young , D. , Nickbarg , E. , Chizzonite , R. , Wolf , S. F. and Trinchieri , G.Production of natural killer cell stimulatory factor (interleukin‐12) by peripheral blood mononuclear cells . J. Exp. Med. , 176 , 1387 – 1398 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. ) Farrar , W. L. , Johnson , H. M. and Farrar , J. J.Regulation of the production of immune interferon and cytotoxic T lymphocytes by interleukin 2 . J. Immunol , 126 , 1120 – 1125 ( 1981. ). [PubMed] [Google Scholar]
  • 27. ) Itoh , K. , Shiba , K. , Shimizu , Y. , Suzuki , R. and Kumagai , K.Generation of activated killer (AK) cells by recombi‐nant interleukin 2 (IL‐2) in collaboration with interferon 7 (IFN‐γ) . J. Immunol , 134 , 3124 – 3129 ( 1985. ). [PubMed] [Google Scholar]
  • 28. ) Roosnek , E. E. , Brouwer , M. C. , Kipp , J. B. and Aarden , L. A.Monocyte‐dependent induction of human peripheral T cells by recombinant interleukin 2 , Eur. J. Immunol , 16 , 35 – 40 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 29. ) Bertagnolli , M. M. , Lin , B.‐Y. , Young , D. and Herrmann , S. H.IL‐12 augments antigen‐dependent proliferation of activated T lymphocytes . J. Immunol. , 149 , 3778 – 3783 ( 1992. ). [PubMed] [Google Scholar]
  • 30. ) Mehrotra , P. T. , Wu , D. , Grim , J. A. , Mostowski , H. S. and Siegel , J. P.Effects of IL‐12 on the generation of cytotoxic activity in human CD8+ T lymphocytes . J. Immunol. , 151 , 2444 – 2452 ( 1993. ). [PubMed] [Google Scholar]
  • 31. ) Gately , M. K. , Wolitzky , A. G. , Quinn , P. M , and Chizzonite , R.Regulation of human cytolytic lymphocyte responses by IL‐12 . Cell. Immunol. , 143 , 127 – 142 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Smyth , M. J. , Strobl , S. L. , Young , H. A. , Ortaldo , J. R. and Ochoa , A. G.Regulation of lymphokine‐activated killer activity and pore‐forming protein gene expression in human blood CD8+ lymphocytes. Inhibition by transforming growth factor‐β , J. Immunol. , 146 , 3289 – 3297 ( 1991. ). [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES