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'Unlicensed' natural killer cells dominate the response to cytomegalovirus infection

Nature Immunology volume 11, pages 321–327 (2010)Cite this article

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Abstract

Natural killer (NK) cells expressing inhibitory receptors that bind to self major histocompatibility complex (MHC) class I are 'licensed', or rendered functionally more responsive to stimulation, whereas 'unlicensed' NK cells lacking receptors for self MHC class I are hyporesponsive. Here we show that contrary to the licensing hypothesis, unlicensed NK cells were the main mediators of NK cell–mediated control of mouse cytomegalovirus infection in vivo. Depletion of unlicensed NK cells impaired control of viral titers, but depletion of licensed NK cells did not. The transfer of unlicensed NK cells was more protective than was the transfer of licensed NK cells. Signaling by the tyrosine phosphatase SHP-1 limited the proliferation of licensed NK cells but not that of unlicensed NK cells during infection. Thus, unlicensed NK cells are critical for protection against viral infection.

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Figure 1: MHC class I inhibition overrides NK cell licensing.
Figure 2: Licensed NK cells become under-represented during MCMV infection.
Figure 3: Ly49C/I is stably expressed and limits the proliferation of NK cells during MCMV infection.
Figure 4: Ly49C/I-mediated inhibition requires functional SHP-1.
Figure 5: Unlicensed NK cells control MCMV infection.
Figure 6: Licensed NK cells do not protect neonates from MCMV infection.

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Acknowledgements

We thank J. Jarjoura for assistance with cell sorting; H. Consengco for assistance with retroviral transduction; H. Robson MacDonald (Ludwig Institute for Cancer Research) for RMA–Hm1-C4 cells; S. Vidal (McGill University) for Ly49H-deficient B6 mice; C. Lowell (University of California, San Francisco) for Me-v B6 mice; and J. Beilke and D. Hesslein for critical reading of the manuscript. Supported by the Cancer Research Institute (M.T.O.), the National Institutes of Health (AI066897) and the American Cancer Society (L.L.L.).

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Authors and Affiliations

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

    Mark T Orr & Lewis L Lanier

  2. Department of Dermatology, University of California, Davis Health System, Sacramento, California, USA

    William J Murphy

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M.T.O. planned and did experiments and wrote the manuscript; W.J.M. contributed to experimental design and provide essential reagents; and L.L.L. contributed to experimental design, data evaluation and writing of the manuscript.

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Correspondence to Lewis L Lanier.

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Orr, M., Murphy, W. & Lanier, L. 'Unlicensed' natural killer cells dominate the response to cytomegalovirus infection. Nat Immunol 11, 321–327 (2010). https://doi.org/10.1038/ni.1849

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