Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1990 Mar 1;171(3):745–762. doi: 10.1084/jem.171.3.745

Cyclosporin A inhibition of interleukin 2 gene expression, but not natural killer cell proliferation, after interferon induction in vivo

PMCID: PMC2187768  PMID: 1689761

Abstract

The IFN inducer, poly(I:C), elicits acute NK cell blastogenesis and proliferation in vivo. The role of IL-2 in mediating this proliferation was investigated in the studies presented here. Blast NK cells were isolated from poly(I:C)-treated, T cell-deficient athymic mice. Dividing cells, incorporating [3H]thymidine, were enriched in the J11d- low density populations isolated from poly(I:C)-treated mice, and were characterized as NK by the following criteria: (a) they were eliminated by treatment with anti-AGM1 in vivo; and (b) they directly mediated lysis of NK-sensitive target cells in a single cell cytotoxicity assay with autoradiography. These poly(I:C)-induced blast NK cells were responsive to IL-2, but, when compared with in vivo activated T cells, responsiveness required 1,000-fold higher concentrations of the factor. The technique of in situ hybridization was used to evaluate induction of IL-2 gene expression after poly(I:C) treatment in vivo. Treatment of euthymic, athymic, and severe combined immunodeficient mice with poly(I:C) activated IL-2 gene expression in a small percentage of spleen leukocytes. The transcription-positive cells were enriched in low density cell populations. These findings demonstrate that IL-2 transcription occurs after IFN induction in vivo, and suggest that an endogenous source of IL-2 exists other than the mature T cell. To assess the IL-2 dependence of in vivo NK cell expansion, poly(I:C)- treated athymic mice were given cyclosporin A (CsA), an agent that regulates IL-2 production at the level of gene transcription. The drug resulted in an 85-100% reduction in the percentages of cells transcribing IL-2. In contrast, CsA administration did not block IFN- enhanced NK cell cytolytic activity, expansion of large granular lymphocyte numbers, or NK cell proliferation. These findings demonstrate that although the proliferation of blast NK cells can be supported by IL-2, IL-2 is not an important mediator of IFN-induced NK cell expansion. Moreover, they establish that the acute proliferation of NK cells in response to IFNs is CsA insensitive.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

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

  1. Biron C. A., Natuk R. J., Welsh R. M. Generation of large granular T lymphocytes in vivo during viral infection. J Immunol. 1986 Mar 15;136(6):2280–2286. [PubMed] [Google Scholar]
  2. Biron C. A., Pedersen K. F., Welsh R. M. Purification and target cell range of in vivo elicited blast natural killer cells. J Immunol. 1986 Jul 15;137(2):463–471. [PubMed] [Google Scholar]
  3. Biron C. A., Sonnenfeld G., Welsh R. M. Interferon induces natural killer cell blastogenesis in vivo. J Leukoc Biol. 1984 Jan;35(1):31–37. doi: 10.1002/jlb.35.1.31. [DOI] [PubMed] [Google Scholar]
  4. Biron C. A., Turgiss L. R., Welsh R. M. Increase in NK cell number and turnover rate during acute viral infection. J Immunol. 1983 Sep;131(3):1539–1545. [PubMed] [Google Scholar]
  5. Biron C. A., Welsh R. M. Blastogenesis of natural killer cells during viral infection in vivo. J Immunol. 1982 Dec;129(6):2788–2795. [PubMed] [Google Scholar]
  6. Biron C. A., Young H. A., Kasaian M. T. Interleukin 2-induced proliferation of murine natural killer cells in vivo. J Exp Med. 1990 Jan 1;171(1):173–188. doi: 10.1084/jem.171.1.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Biron C. A., van den Elsen P., Tutt M. M., Medveczky P., Kumar V., Terhorst C. Murine natural killer cells stimulated in vivo do not express the T cell receptor alpha, beta, gamma, T3 delta, or T3 epsilon genes. J Immunol. 1987 Sep 1;139(5):1704–1710. [PubMed] [Google Scholar]
  8. Bruce J., Symington F. W., McKearn T. J., Sprent J. A monoclonal antibody discriminating between subsets of T and B cells. J Immunol. 1981 Dec;127(6):2496–2501. [PubMed] [Google Scholar]
  9. Dorshkind K., Pollack S. B., Bosma M. J., Phillips R. A. Natural killer (NK) cells are present in mice with severe combined immunodeficiency (scid). J Immunol. 1985 Jun;134(6):3798–3801. [PubMed] [Google Scholar]
  10. Elliott J. F., Lin Y., Mizel S. B., Bleackley R. C., Harnish D. G., Paetkau V. Induction of interleukin 2 messenger RNA inhibited by cyclosporin A. Science. 1984 Dec 21;226(4681):1439–1441. doi: 10.1126/science.6334364. [DOI] [PubMed] [Google Scholar]
  11. Fuse A., Fujita T., Yasumitsu H., Kashima N., Hasegawa K., Taniguchi T. Organization and structure of the mouse interleukin-2 gene. Nucleic Acids Res. 1984 Dec 21;12(24):9323–9331. doi: 10.1093/nar/12.24.9323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hackett J., Jr, Bosma G. C., Bosma M. J., Bennett M., Kumar V. Transplantable progenitors of natural killer cells are distinct from those of T and B lymphocytes. Proc Natl Acad Sci U S A. 1986 May;83(10):3427–3431. doi: 10.1073/pnas.83.10.3427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Henney C. S., Kuribayashi K., Kern D. E., Gillis S. Interleukin-2 augments natural killer cell activity. Nature. 1981 May 28;291(5813):335–338. doi: 10.1038/291335a0. [DOI] [PubMed] [Google Scholar]
  14. Kalman V. K., Klimpel G. R. Cyclosporin A inhibits the production of gamma interferon (IFN gamma), but does not inhibit production of virus-induced IFN alpha/beta. Cell Immunol. 1983 May;78(1):122–129. doi: 10.1016/0008-8749(83)90265-4. [DOI] [PubMed] [Google Scholar]
  15. Kasahara T., Djeu J. Y., Dougherty S. F., Oppenheim J. J. Capacity of human large granular lymphocytes (LGL) to produce multiple lymphokines: interleukin 2, interferon, and colony stimulating factor. J Immunol. 1983 Nov;131(5):2379–2385. [PubMed] [Google Scholar]
  16. Kasai M., Iwamori M., Nagai Y., Okumura K., Tada T. A glycolipid on the surface of mouse natural killer cells. Eur J Immunol. 1980 Mar;10(3):175–180. doi: 10.1002/eji.1830100304. [DOI] [PubMed] [Google Scholar]
  17. Kasaian M. T., Biron C. A. The activation of IL-2 transcription in L3T4+ and Lyt-2+ lymphocytes during virus infection in vivo. J Immunol. 1989 Feb 15;142(4):1287–1292. [PubMed] [Google Scholar]
  18. Krönke M., Leonard W. J., Depper J. M., Arya S. K., Wong-Staal F., Gallo R. C., Waldmann T. A., Greene W. C. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5214–5218. doi: 10.1073/pnas.81.16.5214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lowenthal J. W., Greene W. C. Contrasting interleukin 2 binding properties of the alpha (p55) and beta (p70) protein subunits of the human high-affinity interleukin 2 receptor. J Exp Med. 1987 Oct 1;166(4):1156–1161. doi: 10.1084/jem.166.4.1156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Migliorati G., Cannarile L., Herberman R. B., Bartocci A., Stanley E. R., Riccardi C. Role of interleukin 2 (IL 2) and hemopoietin-1 (H-1) in the generation of mouse natural killer (NK) cells from primitive bone marrow precursors. J Immunol. 1987 Jun 1;138(11):3618–3625. [PubMed] [Google Scholar]
  21. Phillips J. H., Takeshita T., Sugamura K., Lanier L. L. Activation of natural killer cells via the p75 interleukin 2 receptor. J Exp Med. 1989 Jul 1;170(1):291–296. doi: 10.1084/jem.170.1.291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Piguet P. F., Grau G., Irle C., Vassalli P. Administration of recombinant interleukin 2 to mice enhances production of hemopoietic and natural killer cells. Eur J Immunol. 1986 Oct;16(10):1257–1261. doi: 10.1002/eji.1830161012. [DOI] [PubMed] [Google Scholar]
  23. Riccardi C., Giampietri A., Migliorati G., Cannarile L., D'Adamio L., Herberman R. B. Generation of mouse natural killer (NK) cell activity: effect of interleukin-2 (IL-2) and interferon (IFN) on the in vivo development of natural killer cells from bone marrow (BM) progenitor cells. Int J Cancer. 1986 Oct 15;38(4):553–562. doi: 10.1002/ijc.2910380416. [DOI] [PubMed] [Google Scholar]
  24. Robb R. J., Greene W. C. Internalization of interleukin 2 is mediated by the beta chain of the high-affinity interleukin 2 receptor. J Exp Med. 1987 Apr 1;165(4):1201–1206. doi: 10.1084/jem.165.4.1201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Santoli D., Trinchieri G., Koprowski H. Cell-mediated cytotoxicity against virus-infected target cells in humans. II. Interferon induction and activation of natural killer cells. J Immunol. 1978 Aug;121(2):532–538. [PubMed] [Google Scholar]
  26. Sixth International Workshop on Natural Killer Cells. Goslar, FRG, July 26-29, 1989. Abstracts. Nat Immun Cell Growth Regul. 1989;8(3):117–152. [PubMed] [Google Scholar]
  27. Suzuki R., Handa K., Itoh K., Kumagai K. Natural killer (NK) cells as a responder to interleukin 2 (IL 2). I. Proliferative response and establishment of cloned cells. J Immunol. 1983 Feb;130(2):981–987. [PubMed] [Google Scholar]
  28. Taira S., Matsui M., Hayakawa K., Yokoyama T., Nariuchi H. Interleukin secretion by B cell lines and splenic B cells stimulated with calcium ionophore and phorbol ester. J Immunol. 1987 Nov 1;139(9):2957–2964. [PubMed] [Google Scholar]
  29. Trinchieri G., Santoli D. Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells. Enhancement of human natural killer cell activity by interferon and antagonistic inhibition of susceptibility of target cells to lysis. J Exp Med. 1978 May 1;147(5):1314–1333. doi: 10.1084/jem.147.5.1314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Tsudo M., Goldman C. K., Bongiovanni K. F., Chan W. C., Winton E. F., Yagita M., Grimm E. A., Waldmann T. A. The p75 peptide is the receptor for interleukin 2 expressed on large granular lymphocytes and is responsible for the interleukin 2 activation of these cells. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5394–5398. doi: 10.1073/pnas.84.15.5394. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Wang H. M., Smith K. A. The interleukin 2 receptor. Functional consequences of its bimolecular structure. J Exp Med. 1987 Oct 1;166(4):1055–1069. doi: 10.1084/jem.166.4.1055. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES