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Efficient generation of human natural killer cell lines by viral transformation

Leukemia volume 28, pages 192–195 (2014)Cite this article

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The short lifespan of human natural killer (NK) cells is one of the major obstacles in human NK cell research and application. Here we describe the in vitro growth transformation of functional human NK cells by Herpesvirus saimiri (HVS), a primate rhadinovirus.

NK cells are non-B, non-T lymphocytes that account for 2–18% of lymphocytes in normal human peripheral blood. They are distinguished by a CD3−CD56+ phenotype and they communicate through interferon-γ and tumor necrosis factor secretion with dendritic cells, macrophages, T cells and endothelial cells. The natural lifespan for NK cells in the human body is 2 weeks.1 In vitro, the lifespan of NK cells can be extended to a few weeks. Only few human permanent NK-like cell lines are available for research. Most of these NK-like cell lines were derived from NK cell leukemia or lymphoma patients, lack important features of natural NK cells, are difficult to cultivate and require supplementation with various cytokines such as interleukin (IL)-2, IL-7, IL-12.2, 3, 4, 5, 6 Several of these NK-like cell lines, like YT and NK-92, are latently infected with Epstein–Barr virus;7 the contribution of viral effectors to cell proliferation and survival has not been studied.

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References

  1. Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S . Functions of natural killer cells. Nat Immunol 2008; 9: 503–510.

    Article  CAS  PubMed  Google Scholar 

  2. Yagita M, Huang CL, Umehara H, Matsuo Y, Tabata R, Miyake M et al. A novel natural killer cell line (KHYG-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation. Leukemia 2000; 14: 922–930.

    Article  CAS  PubMed  Google Scholar 

  3. Gong JH, Maki G, Klingemann HG . Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 1994; 8: 652–658.

    CAS  PubMed  Google Scholar 

  4. Yodoi J, Teshigawara K, Nikaido T, Fukui K, Noma T, Honjo T et al. TCGF (IL 2)-receptor inducing factor(s). I. Regulation of IL 2 receptor on a natural killer-like cell line (YT cells). J Immunol 1985; 134: 1623–1630.

    CAS  PubMed  Google Scholar 

  5. Kornbluth J, Flomenberg N, Dupont B . Cell surface phenotype of a cloned line of human natural killer cells. J Immunol 1982; 129: 2831–2837.

    CAS  PubMed  Google Scholar 

  6. Robertson MJ, Cochran KJ, Cameron C, Le JM, Tantravahi R, Ritz J . Characterization of a cell line, NKL, derived from an aggressive human natural killer cell leukemia. Exp Hematol 1996; 24: 406–415.

    CAS  PubMed  Google Scholar 

  7. Uphoff CC, Denkmann SA, Steube KG, Drexler HG . Detection of EBV, HBV, HCV, HIV-1, HTLV-I and -II, and SMRV in human and other primate cell lines. J Biomed Biotechnol 2010; 2010: 904767.

    Article  PubMed  Google Scholar 

  8. Biesinger B, Mueller-Fleckenstein I, Simmer B, Lang G, Wittmann S, Platzer E et al. Stable growth transformation of human T lymphocytes by herpesvirus saimiri. Proc Natl Acad Sci USA 1992; 89: 3116–3119.

    Article  CAS  PubMed  Google Scholar 

  9. Heck E, Friedrich U, Gack MU, Lengenfelder D, Schmidt M, Mueller-Fleckenstein I et al. Growth transformation of human T cells by herpesvirus saimiri requires multiple Tip-Lck interaction motifs. J Virol 2006; 80: 9934–9942.

    Article  CAS  PubMed  Google Scholar 

  10. Stephan V, Wahn V, Le DF, Dirksen U, Broker B, Mueller-Fleckenstein I et al. Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med 1996; 335: 1563–1567.

    Article  CAS  PubMed  Google Scholar 

  11. Pacheco-Castro A, Al varez-Zapata D, Serrano-Torres P, Regueiro JR . Signaling through a CD3 gamma-deficient TCR/CD3 complex in immortalized mature CD4+ and CD8+ T lymphocytes. J Immunol 1998; 161: 3152–3160.

    CAS  PubMed  Google Scholar 

  12. Crequer A, Troeger A, Patin E, Ma CS, Picard C, Pedergnana V et al. Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections. J Clin Invest 2012; 122: 3239–3247.

    Article  CAS  PubMed  Google Scholar 

  13. Zielke K, Full F, Teufert N, Schmidt M, Mueller-Fleckenstein I, Alberter B et al. The insulator protein CTCF binding sites in the orf73/LANA promoter region of herpesvirus saimiri are involved in conferring episomal stability in latently infected human T cells. J Virol 2012; 86: 1862–1873.

    Article  CAS  PubMed  Google Scholar 

  14. Toptan T, Ensser A, Fickenscher H . Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells. Gene Ther 2010; 17: 653–661.

    Article  CAS  PubMed  Google Scholar 

  15. Knappe A, Feldmann G, Dittmer U, Meinl E, Nisslein T, Wittmann S et al. Herpesvirus saimiri-transformed macaque T cells are tolerated and do not cause lymphoma after autologous reinfusion. Blood 2000; 95: 3256–3261.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Monika Schmidt, Doris Lengenfelder and Brigitte Scholz for tissue culture advice and Bernhard Fleckenstein for helpful discussions and continuous support. We thank Georg Fey for ARH77 and SEM cells. This work was supported by grants to AE by DFG collaborative research center SFB796 and international graduate school GRK 1071, and the Wilhelm Sander Stiftung 2009.002.1, and the ‘Novartis Stiftung für therapeutische Forschung’ for providing an individual fellowship to FF.

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  1. Institut für Klinische und Molekulare Virologie der Friedrich-Alexander Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Erlangen, Germany

    B Vogel, K Tennert, F Full & A Ensser

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  1. B Vogel
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  2. K Tennert
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  3. F Full
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  4. A Ensser
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Correspondence to A Ensser.

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Competing interests

Benjamin Vogel and Armin Ensser filed a patent to the German Patent Office involving applications of virus-transformed NK cells. This does not alter our adherence to all Leukemia policies on sharing data and materials.

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BV carried out the experiments, KT and FF provided important reagents, BV and AE designed the experiments and wrote the paper.

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Vogel, B., Tennert, K., Full, F. et al. Efficient generation of human natural killer cell lines by viral transformation. Leukemia 28, 192–195 (2014). https://doi.org/10.1038/leu.2013.188

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