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. 1980 Mar 1;151(3):614–627. doi: 10.1084/jem.151.3.614

Increased sensitivity of human lymphoid lines to natural killer cells after induction of the Epstein-Barr viral cycle by superinfection or sodium butyrate

PMCID: PMC2185807  PMID: 6244358

Abstract

Superinfection of latently Epstein-Barr virus (EBV)-carrying Raji cells with the P3HR-1 substrain EBV, known to induce the entry of a substantial fraction of cells into an abortively lytic cycle, increased the susceptibility of the cells to natural killer (NK) effect of human blood lymphocytes. Reciprocal cold-target competition tests with known NK-cell sensitive and -resistant lymphoid cell ines showed that the increased susceptibility is a result of the appearance of an NK- sensitive target, rather than to a general increase in membrane fragility. Lymphocytes of EBV-seropositive and -negative donors were equally effective killers against P3HR-1 virus-superinfected targets. EBV-induced NK sensitivity increased with time. It was a result of some event associated with the intracellular viral cycle, and not to the adherence of viral particles to the cell surface. Induction of EBV- carrying P3HR-1 cells to entry into the viral cycle with n-butyrate also increased their NK sensitivity. A transforming, noncytopathic prototype strain of EBV, B95-8, failed to increase the susceptibility of theRaji cells to NK-lysis, although it had some effect on the Daudi line. Because NK cells can kill virus-producing cells at an early stage of the cycle, before the virus particles are assembled, they may restrict, in vivo, the spread of the virus from latently infected cells.

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Selected References

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  1. Andersson T., Stejskal V., Harfast B. An in vitro method for study of human lymphocyte cytotoxicity against mumps-virus-infected target cells. J Immunol. 1975 Jan;114(1 Pt 1):237–243. [PubMed] [Google Scholar]
  2. Bakacs T., Gergely P., Klein E. Characterization of cytotoxic human lymphocyte subpopulations: the role of Fc-receptor-carrying cells. Cell Immunol. 1977 Aug;32(2):317–328. doi: 10.1016/0008-8749(77)90208-8. [DOI] [PubMed] [Google Scholar]
  3. Bakács T., Klein E., Yefenof E., Gergely P., Steinitz M. Human blood lymphocyte fractionation with special attention to their cytotoxic potential. Z Immunitatsforsch Immunobiol. 1978 Mar;154(2):121–134. [PubMed] [Google Scholar]
  4. Brown T. D., Rickwood D., MacGillivray A. J., Klein G. Studies of Epstein-Barr virus (EBV)-associated nuclear antigen: solubilization from Raji cell chromatin with 5 M-urea-2 M-nacl and fractionation on hydroxyapatite. J Gen Virol. 1978 Sep;40(3):511–517. doi: 10.1099/0022-1317-40-3-511. [DOI] [PubMed] [Google Scholar]
  5. Diehl V., Henle G., Henle W., Kohn G. Demonstration of a herpes group virus in cultures of peripheral leukocytes from patients with infectious mononucleosis. J Virol. 1968 Jul;2(7):663–669. doi: 10.1128/jvi.2.7.663-669.1968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dölken G., Klein G. Expression of Epstein-Barr-virus-associated membrane antigen in Raji cells superinfected with two different virus strains. Virology. 1976 Mar;70(1):210–213. doi: 10.1016/0042-6822(76)90255-5. [DOI] [PubMed] [Google Scholar]
  7. Epstein M. A., Achong B. G., Barr Y. M., Zajac B., Henle G., Henle W. Morphological and virological investigations on cultured Burkitt tumor lymphoblasts (strain Raji). J Natl Cancer Inst. 1966 Oct;37(4):547–559. [PubMed] [Google Scholar]
  8. Hampar B., Derge J. G., Martos L. M., Walker J. L. Synthesis of Epstein-Barr virus after activation of the viral genome in a "virus-negative" human lymphoblastoid cell (Raji) made resistant to 5-bromodeoxyuridine (thymidine kinase-virus antigen-immunofluorescence-herpesvirus fingerprints). Proc Natl Acad Sci U S A. 1972 Jan;69(1):78–82. doi: 10.1073/pnas.69.1.78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hampar B., Lenoir G., Nonoyama M., Derger J. G., Chang S. Cell cycle dependence for activation of Epstein-Barr virus by inhibitors of protein synthesis or medium deficient in arginine. Virology. 1976 Feb;69(2):660–668. doi: 10.1016/0042-6822(76)90494-3. [DOI] [PubMed] [Google Scholar]
  10. Henle W., Henle G., Zajac B. A., Pearson G., Waubke R., Scriba M. Differential reactivity of human serums with early antigens induced by Epstein-Barr virus. Science. 1970 Jul 10;169(3941):188–190. doi: 10.1126/science.169.3941.188. [DOI] [PubMed] [Google Scholar]
  11. Herberman R. B., Nunn M. E., Holden H. T., Lavrin D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer. 1975 Aug 15;16(2):230–239. doi: 10.1002/ijc.2910160205. [DOI] [PubMed] [Google Scholar]
  12. Herberman R. B., Nunn M. E., Holden H. T. Low density of Thy 1 antigen on mouse effector cells mediating natural cytotoxicity against tumor cells. J Immunol. 1978 Jul;121(1):304–309. [PubMed] [Google Scholar]
  13. Herberman R. B., Nunn M. E., Holden H. T., Staal S., Djeu J. Y. Augmentation of natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic target cells. Int J Cancer. 1977 Apr 15;19(4):555–564. doi: 10.1002/ijc.2910190417. [DOI] [PubMed] [Google Scholar]
  14. Jondal M., Pross H. Surface markers on human b and t lymphocytes. VI. Cytotoxicity against cell lines as a functional marker for lymphocyte subpopulations. Int J Cancer. 1975 Apr 15;15(4):596–605. doi: 10.1002/ijc.2910150409. [DOI] [PubMed] [Google Scholar]
  15. Kiessling R., Klein E., Wigzell H. "Natural" killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol. 1975 Feb;5(2):112–117. doi: 10.1002/eji.1830050208. [DOI] [PubMed] [Google Scholar]
  16. Klein E., Klein G., Nadkarni J. S., Nadkarni J. J., Wigzell H., Clifford P. Surface IgM-kappa specificity on a Burkitt lymphoma cell in vivo and in derived culture lines. Cancer Res. 1968 Jul;28(7):1300–1310. [PubMed] [Google Scholar]
  17. Klein G., Dombos L., Gothoskar B. Sensitivity of Epstein-Barr virus (EBV) producer and non-producer human lymphoblastoid cell lines to superinfection with EB-virus. Int J Cancer. 1972 Jul 15;10(1):44–57. doi: 10.1002/ijc.2910100108. [DOI] [PubMed] [Google Scholar]
  18. Klein G., Dombos L. Relationship between the sensitivity of EBV-carrying lymphoblastoid lines to superinfection and the inducibility of the resident viral genome. Int J Cancer. 1973 Mar 15;11(2):327–337. doi: 10.1002/ijc.2910110210. [DOI] [PubMed] [Google Scholar]
  19. Klein G., Giovanella B., Westman A., Stehlin J. S., Mumford D. An EBV-genome-negative cell line established from an American Burkitt lymphoma; receptor characteristics. EBV infectibility and permanent conversion into EBV-positive sublines by in vitro infection. Intervirology. 1975;5(6):319–334. doi: 10.1159/000149930. [DOI] [PubMed] [Google Scholar]
  20. Klein G., Lindahl T., Jondal M., Leibold W., Menézes J., Nilsson K., Sundström C. Continuous lymphoid cell lines with characteristics of B cells (bone-marrow-derived), lacking the Epstein-Barr virus genome and derived from three human lymphomas. Proc Natl Acad Sci U S A. 1974 Aug;71(8):3283–3286. doi: 10.1073/pnas.71.8.3283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lindahl P., Leary P., Gresser I. Enhancement by interferon of the specific cytotoxicity of sensitized lymphocytes. Proc Natl Acad Sci U S A. 1972 Mar;69(3):721–725. doi: 10.1073/pnas.69.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lozzio C. B., Lozzio B. B. Cytotoxicity of a factor isolated from human spleen. J Natl Cancer Inst. 1973 Feb;50(2):535–538. doi: 10.1093/jnci/50.2.535. [DOI] [PubMed] [Google Scholar]
  23. Minato N., Bloom B. R., Jones C., Holland J., Reid L. M. Mechanism of rejection of virus persistently infected tumor cells by athymic nude mice. J Exp Med. 1979 May 1;149(5):1117–1133. doi: 10.1084/jem.149.5.1117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Minowada J., Onuma T., Moore G. E. Rosette-forming human lymphoid cell lines. I. Establishment and evidence for origin of thymus-derived lymphocytes. J Natl Cancer Inst. 1972 Sep;49(3):891–895. [PubMed] [Google Scholar]
  25. Nonoyama M., Pagano J. S. Detection of Epstein-Barr viral genome in nonproductive cells. Nat New Biol. 1971 Sep 22;233(38):103–106. doi: 10.1038/newbio233103a0. [DOI] [PubMed] [Google Scholar]
  26. Pearson G. R., Johansson B., Klein G. Antibody-dependent cellular cytotoxicity against Epstein-Barr virus-associated antigens in African patients with nasopharyngeal carcinoma. Int J Cancer. 1978 Aug 15;22(2):120–125. doi: 10.1002/ijc.2910220203. [DOI] [PubMed] [Google Scholar]
  27. Peter H. H., Knoop F., Kalden J. R. Spontaneous and antibody-dependent cellular cytotoxicity in melanoma patients and healthy control presons. Z Immunitatsforsch Exp Klin Immunol. 1976 Apr;151(3):263–281. [PubMed] [Google Scholar]
  28. Reedman B. M., Klein G. Cellular localization of an Epstein-Barr virus (EBV)-associated complement-fixing antigen in producer and non-producer lymphoblastoid cell lines. Int J Cancer. 1973 May;11(3):499–520. doi: 10.1002/ijc.2910110302. [DOI] [PubMed] [Google Scholar]
  29. Santoli D., Koprowski H. Mechanisms of activation of human natural killer cells against tumor and virus-infected cells. Immunol Rev. 1979;44:125–163. doi: 10.1111/j.1600-065x.1979.tb00269.x. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Santoli D., Trinchieri G., Lief F. S. Cell-mediated cytotoxicity against virus-infected target cells in humans. I. Characterization of the effector lymphocyte. J Immunol. 1978 Aug;121(2):526–531. [PubMed] [Google Scholar]
  32. Skurzak H., Steiner L., Klein E., Lamon E. Cytotoxicity of human peripheral lymphocytes for glioma, osteosarcoma, and glia cell lines. Natl Cancer Inst Monogr. 1973 Jun;37:93–102. [PubMed] [Google Scholar]
  33. Takasugi M., Mickey M. R., Terasaki P. I. Reactivity of lymphocytes from normal persons on cultured tumor cells. Cancer Res. 1973 Nov;33(11):2898–2902. [PubMed] [Google Scholar]
  34. West W. H., Cannon G. B., Kay H. D., Bonnard G. D., Herberman R. B. Natural cytotoxic reactivity of human lymphocytes against a myeloid cell line: characterization of effector cells. J Immunol. 1977 Jan;118(1):355–361. [PubMed] [Google Scholar]
  35. Zinkernagel R. M., Doherty P. C. Cytotoxic thymus-derived lymphocytes in cerebrospinal fluid of mice with lymphocytic choriomeningitis. J Exp Med. 1973 Nov 1;138(5):1266–1269. doi: 10.1084/jem.138.5.1266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Zur Hausen H., Schulte-Holthausen H. Presence of EB virus nucleic acid homology in a "virus-free" line of Burkitt tumour cells. Nature. 1970 Jul 18;227(5255):245–248. doi: 10.1038/227245a0. [DOI] [PubMed] [Google Scholar]
  37. de Vries J. E., Meyering M., van Dongen A., Rümke P. The influence of different isolation procedures and the use of target cells from melanoma cell lines and short-term cultures on the non-specific cytotoxic effects of lymphocytes from healthy donors. Int J Cancer. 1975 Mar 15;15(3):391–400. doi: 10.1002/ijc.2910150305. [DOI] [PubMed] [Google Scholar]
  38. zur Hansen H., Diehl V., Wolf H., Schulte-Holthausen H., Schneider U. Occurrence of Epstein-Barr virus genomes in human lymphoblastoid cell lines. Nat New Biol. 1972 Jun 7;237(75):189–190. doi: 10.1038/newbio237189a0. [DOI] [PubMed] [Google Scholar]

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