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.

Adaptive immune features of natural killer cells

Nature volume 457, pages 557–561 (2009)Cite this article

An Erratum to this article was published on 26 February 2009

Abstract

In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing ‘memory’ NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Figure 1: Preferential expansion of wild-type, but not DAP12-deficient, NK cells during MCMV infection.
Figure 2: Robust proliferation of adoptively transferred wild-type NK cells in DAP12-deficient mice after MCMV infection.
Figure 3: Expansion and contraction of NK cells in lymphoid and non-lymphoid tissues results in ‘memory’ NK cells.
Figure 4: Function and phenotype of ‘memory’ NK cells.
Figure 5: Secondary expansion and protective immunity in ‘memory’ NK cells.

References

  1. Harty, J. T. & Badovinac, V. P. Shaping and reshaping CD8+ T-cell memory. Nature Rev. Immunol. 8, 107–119 (2008)

    CAS  Article  Google Scholar 

  2. Kaech, S. M., Wherry, E. J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nature Rev. Immunol. 2, 251–262 (2002)

    CAS  Article  Google Scholar 

  3. Sprent, J. & Surh, C. D. T cell memory. Annu. Rev. Immunol. 20, 551–579 (2002)

    CAS  Article  Google Scholar 

  4. Williams, M. A. & Bevan, M. J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007)

    CAS  Article  Google Scholar 

  5. Butz, E. A. & Bevan, M. J. Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. Immunity 8, 167–175 (1998)

    CAS  Article  Google Scholar 

  6. Goldrath, A. W. & Bevan, M. J. Selecting and maintaining a diverse T-cell repertoire. Nature 402, 255–262 (1999)

    ADS  CAS  Article  Google Scholar 

  7. Murali-Krishna, K. et al. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8, 177–187 (1998)

    CAS  Article  Google Scholar 

  8. Badovinac, V. P., Porter, B. B. & Harty, J. T. Programmed contraction of CD8+ T cells after infection. Nature Immunol. 3, 619–626 (2002)

    CAS  Article  Google Scholar 

  9. Jameson, S. C. Maintaining the norm: T-cell homeostasis. Nature Rev. Immunol. 2, 547–556 (2002)

    CAS  Article  Google Scholar 

  10. Marrack, P. & Kappler, J. Control of T cell viability. Annu. Rev. Immunol. 22, 765–787 (2004)

    CAS  Article  Google Scholar 

  11. Schluns, K. S. & Lefrancois, L. Cytokine control of memory T-cell development and survival. Nature Rev. Immunol. 3, 269–279 (2003)

    CAS  Article  Google Scholar 

  12. Lefrancois, L. & Masopust, D. T cell immunity in lymphoid and non-lymphoid tissues. Curr. Opin. Immunol. 14, 503–508 (2002)

    CAS  Article  Google Scholar 

  13. Masopust, D., Vezys, V., Marzo, A. L. & Lefrancois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001)

    ADS  CAS  Article  Google Scholar 

  14. Lanier, L. L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005)

    CAS  Article  Google Scholar 

  15. Lanier, L. L. Back to the future—defining NK cells and T cells. Eur. J. Immunol. 37, 1424–1426 (2007)

    CAS  Article  Google Scholar 

  16. Glas, R. et al. Recruitment and activation of natural killer (NK) cells in vivo determined by the target cell phenotype. An adaptive component of NK cell-mediated responses. J. Exp. Med. 191, 129–138 (2000)

    CAS  Article  Google Scholar 

  17. O’Leary, J. G., Goodarzi, M., Drayton, D. L. & von Andrian, U. H. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nature Immunol. 7, 507–516 (2006)

    Article  Google Scholar 

  18. Arase, H. et al. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002)

    ADS  CAS  Article  Google Scholar 

  19. Brown, M. G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001)

    ADS  CAS  Article  Google Scholar 

  20. Daniels, K. A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194, 29–44 (2001)

    CAS  Article  Google Scholar 

  21. Smith, H. R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl Acad. Sci. USA 99, 8826–8831 (2002)

    ADS  CAS  Article  Google Scholar 

  22. Vidal, S. M. & Lanier, L. L. NK cell recognition of mouse cytomegalovirus-infected cells. Curr. Top. Microbiol. Immunol. 298, 183–206 (2006)

    CAS  PubMed  Google Scholar 

  23. Dokun, A. O. et al. Specific and nonspecific NK cell activation during virus infection. Nature Immunol. 2, 951–956 (2001)

    CAS  Article  Google Scholar 

  24. Yokoyama, W. M., Kim, S. & French, A. R. The dynamic life of natural killer cells. Annu. Rev. Immunol. 22, 405–429 (2004)

    CAS  Article  Google Scholar 

  25. Bakker, A. B. et al. DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13, 345–353 (2000)

    CAS  Article  Google Scholar 

  26. Homann, D., Teyton, L. & Oldstone, M. B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nature Med. 7, 913–919 (2001)

    CAS  Article  Google Scholar 

  27. Williams, M. A., Ravkov, E. V. & Bevan, M. J. Rapid culling of the CD4+ T cell repertoire in the transition from effector to memory. Immunity 28, 533–545 (2008)

    CAS  Article  Google Scholar 

  28. Stetson, D. B. et al. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003)

    CAS  Article  Google Scholar 

  29. Badovinac, V. P., Messingham, K. A., Hamilton, S. E. & Harty, J. T. Regulation of CD8+ T cells undergoing primary and secondary responses to infection in the same host. J. Immunol. 170, 4933–4942 (2003)

    CAS  Article  Google Scholar 

  30. Belz, G. T. et al. Minimal activation of memory CD8+ T cell by tissue-derived dendritic cells favors the stimulation of naive CD8+ T cells. Nature Immunol. 8, 1060–1066 (2007)

    CAS  Article  Google Scholar 

  31. Grayson, J. M. et al. Differential sensitivity of naive and memory CD8+ T cells to apoptosis in vivo . J. Immunol. 169, 3760–3770 (2002)

    CAS  Article  Google Scholar 

  32. Jabbari, A. & Harty, J. T. Secondary memory CD8+ T cells are more protective but slower to acquire a central-memory phenotype. J. Exp. Med. 203, 919–932 (2006)

    CAS  Article  Google Scholar 

  33. Zimmermann, C., Prevost-Blondel, A., Blaser, C. & Pircher, H. Kinetics of the response of naive and memory CD8 T cells to antigen: similarities and differences. Eur. J. Immunol. 29, 284–290 (1999)

    CAS  Article  Google Scholar 

  34. Bukowski, J. F., Warner, J. F., Dennert, G. & Welsh, R. M. Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo . J. Exp. Med. 161, 40–52 (1985)

    CAS  Article  Google Scholar 

  35. Sun, J. C. & Bevan, M. J. Cutting edge: long-lived CD8 memory and protective immunity in the absence of CD40 expression on CD8 T cells. J. Immunol. 172, 3385–3389 (2004)

    CAS  Article  Google Scholar 

  36. Bubic, I. et al. Gain of virulence caused by loss of a gene in murine cytomegalovirus. J. Virol. 78, 7536–7544 (2004)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the Lanier laboratory for comments and discussions, and R. Locksley and W. Seaman for critical reading of this manuscript. The work was supported by National Institutes of Health grant AI068129. J.C.S. is supported by the Irvington Institute for Immunological Research. J.N.B. is supported by the Juvenile Diabetes Research Foundation. L.L.L. is an American Cancer Society Research Professor.

Author Contributions J.C.S. and J.N.B. contributed to project planning, experimental work, data analysis and writing the manuscript. L.L.L. contributed to project planning, data analysis and writing the manuscript.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, California 94143, USA,

    Joseph C. Sun, Joshua N. Beilke & Lewis L. Lanier

Authors
  1. Joseph C. Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua N. Beilke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lewis L. Lanier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lewis L. Lanier.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-5 with Legends (PDF 192 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sun, J., Beilke, J. & Lanier, L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009). https://doi.org/10.1038/nature07665

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07665

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing