Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Baculovirus directly activates murine NK cells via TLR9

Cancer Gene Therapy volume 24, pages 175–179 (2017)Cite this article

Subjects

Abstract

The importance of natural killer (NK) cells in innate immune responses against tumors or viral infections enhances the appeal of NK cell-based immunotherapeutic approaches. We have recently reported that baculovirus (BV)-infected dendritic cells (DCs; BV-DCs) induce antitumor immunity against established tumors in mice. These antitumor effects were CD8+ T-cell and NK cell dependent; however, they were found to be CD4+ T-cell independent. In this study, we investigated the involvement of Toll-like receptor 9 (TLR9) in the process of BV recognition by NK cells. We found that BV directly stimulated NK cells, induced the expression of the activation marker CD69 and promoted interferon-gamma (IFN-γ) production and cytotoxicity. Moreover, TLR9 knockout in mice (tlr9−/− NK cells) inhibited NK cell responses to BV, indicating that TLR9 may have a relevant role in the BV-induced upregulation of NK cell functions. Our data demonstrated for the first time that NK cells directly recognize BV via TLR9, which provides opportunities for the use of this technique as an effective tool for BV-based immunotherapies against malignancies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Kitajima M, Abe T, Miyano-Kurosaki N, Taniguchi M, Nakayama T, Takaku H . Induction of natural killer cells-dependent antitumor immunity by the Autographa californica multiple nuclear polyhedrosis virus. Mol Ther 2008; 16: 261–268.

    Article  CAS  Google Scholar 

  2. Nishibe Y, Kaneko H, Suzuki H, Abe T, Matsuura Y, Takaku H . Baculovirus–mediated interferon alleviates dimethylnitrosamine-induced liver cirrhosis symptoms in a murine model. Gene Ther 2008; 15: 990–997.

    Article  CAS  Google Scholar 

  3. Suzuki T, Oo Chang M, Kitajima M, Takaku H . Induction of antitumor immunity against mouse carcinoma by baculovirus-infected dendritic cells. Cell Mol Immunol 2010; 7: 440–446.

    Article  CAS  Google Scholar 

  4. Fujihira A, Suzuki T, Chang MO, Moriyama T, Kitajima M, Takaku H . Antitumor effects of baculovirus-infected dendritic cells against human pancreatic carcinoma. Gene Ther 2014; 21: 849–854.

    Article  CAS  Google Scholar 

  5. Molinari P, Crespo MI, Gravisaco MJ, Taboga O, Morón G . Baculovirus capsid display potentiates OVA cytotoxic and innate immune responses. PLoS ONE 2011; 6: 8.

    Article  Google Scholar 

  6. Lee SH, Miyagi T, Biron CA . Keeping NK cells in highly regulated antiviral warfare. Trends Immunol 2007; 28: 252–259.

    Article  CAS  Google Scholar 

  7. Sun C, Beilke JN, Lanier LL . Adaptive immune features of natural killer cells. Nature 2009; 457: 557–561.

    Article  CAS  Google Scholar 

  8. Vivier E, Ugolini S . Natural killer cells: from basic research to treatments. Front Immunol 2011; 2: 18.

    Article  Google Scholar 

  9. Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L . Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol 2012; 12: 239–252.

    Article  CAS  Google Scholar 

  10. Romagne F, Vivier E . Natural killer cell-based therapies. F1000 Med Rep 2013; 3: 9.

    Google Scholar 

  11. Orange JS . Natural killer cell deficiency. J Allergy Clin Immunol 2013; 32: 515–525.

    Article  Google Scholar 

  12. Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, Deng W et al. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol 2014; 122: 91–128.

    Article  CAS  Google Scholar 

  13. Cerwenka A, Lanier LL . Natural killer cell memory in infection, inflammation and cancer. Nat Rev Immunol 2016; 16: 112–123.

    Article  CAS  Google Scholar 

  14. Orange JS . Human natural killer cell deficiencies. Curr Opin Allergy Clin Immunol 2006; 6: 399–409.

    Article  Google Scholar 

  15. Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K . Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 2000; 356: 1795–1799.

    Article  CAS  Google Scholar 

  16. Hokland H, Kjaergaard J, Kuppen PJ, Nannmark U, Agger R, Hokland P et al. Endogenous and adoptively transferred A-NK and T-LAK cells continuously accumulate within murine metastases up to 48 h after inoculation. In Vivo 1999; 13: 199–204.

    CAS  PubMed  Google Scholar 

  17. Stewart CA, Vivier E . Strategies of NK cell recognition and their roles in tumor immunosurveillance In: Kitamura D (ed). How the Immune System Recognizes Self and Nonself: Immunoreceptors and Their Signaling. Springer: Tokyo, Japan, 2007, pp 37–81.

    Google Scholar 

  18. Meinhardt K, Kroeger I, Abendroth A, Müller S, Mackensen A, Ullrich E . Influence of NK cell magnetic bead isolation methods on phenotype and function of murine NK cells. J Immunol Meth 2012; 378: 1–10.

    Article  CAS  Google Scholar 

  19. Abe T, Kaname Y, Wen X, Tani H, Moriishi K, Uematsu S et al. Baculovirus induces type I interferon production through Toll-Like receptor-dependent and -independent pathways in a cell-type-specific manner. J Virol 2009; 83: 7629–7640.

    Article  CAS  Google Scholar 

  20. Abe T, Hemmi H, Miyamoto H, Moriishi K, Tamura S, Takaku H et al. Involvement of the Toll-Like Receptor 9 signaling pathway in the induction of innate immunity by baculovirus. J Virol 2005; 79: 2847–2858.

    Article  CAS  Google Scholar 

  21. Abe T, Matsuura Y . Host innate immune responses induced by baculovirus in mammals. Curr Gene Ther 2010; 10: 226–231.

    Article  CAS  Google Scholar 

  22. Esin S, Batoni G, Pardini M, Favilli F, Bottai D, Maisetta G et al. Functional characterization of human natural killer cells responding to Mycobacterium bovis bacille Calmette-Guerin. Immunology 2004; 112: 143–152.

    Article  CAS  Google Scholar 

  23. Marcenaro E, Ferranti B, Falco M, Moretta L, Moretta A . Human NK cells directly recognize Mycobacterium bovis via TLR2 and acquire the ability to kill monocyte-derived DC. Int Immunol 2008; 20: 1155–1167.

    Article  CAS  Google Scholar 

  24. Esin S, Counoupas C, Aulicino A, Brancatisano FL, Maisetta G, Bottai D et al. Interaction of Mycobacterium tuberculosis cell wall components with the human natural killer cell receptors NKp44 and Toll-like receptor 2. Scand J Immunol 2013; 77: 460–499.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Fujihira for providing excellent technical assistance. We thank Professor N Miyano-Kurosaki for discussions and for comments on the manuscript. This work was supported, in part, by a grant from the Supporting Program for Creating University Ventures from the Japanese Science and Technology Agency, a grant from the Research and Development Program for New Bio-industry Initiatives from the Ministry of Agriculture and Forestry and the Fisheries of Japan, and a Grant-in-Aid for High Technology Research (No. 09309011) from the Ministry of Education, Science, Sports and Culture of Japan.

Author information

Authors and Affiliations

  1. Department of Life and Environmental Sciences, Chiba Institute of Technology, Narashino, Chiba, Japan

    T Moriyama, T Suzuki & M O Chang

  2. Department of Immunology and Pathology, Research Institute National Center for Global Health and Medicine, Ichikawa, Chiba, Japan

    M Kitajima

  3. Research Institute, Chiba Institute of Technology, Narashino, Chiba, Japan

    H Takaku

Authors
  1. T Moriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M O Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Kitajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Takaku
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Takaku.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moriyama, T., Suzuki, T., Chang, M. et al. Baculovirus directly activates murine NK cells via TLR9. Cancer Gene Ther 24, 175–179 (2017). https://doi.org/10.1038/cgt.2017.2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2017.2

This article is cited by

Search

Advanced search

Quick links