Licensing of natural killer cells by host major histocompatibility complex class I molecules

Abstract

Self versus non-self discrimination is a central theme in biology from plants1 to vertebrates, and is particularly relevant for lymphocytes that express receptors capable of recognizing self-tissues and foreign invaders. Comprising the third largest lymphocyte population, natural killer (NK) cells recognize and kill cellular targets and produce pro-inflammatory cytokines. These potentially self-destructive effector functions can be controlled by inhibitory receptors for the polymorphic major histocompatibility complex (MHC) class I molecules that are ubiquitously expressed on target cells2,3,4. However, inhibitory receptors are not uniformly expressed on NK cells, and are germline-encoded by a set of polymorphic genes that segregate independently from MHC genes5,6. Therefore, how NK-cell self-tolerance arises in vivo is poorly understood. Here we demonstrate that NK cells acquire functional competence through ‘licensing’ by self-MHC molecules. Licensing involves a positive role for MHC-specific inhibitory receptors and requires the cytoplasmic inhibitory motif originally identified in effector responses. This process results in two types of self-tolerant NK cells—licensed or unlicensed—and may provide new insights for exploiting NK cells in immunotherapy. This self-tolerance mechanism may be more broadly applicable within the vertebrate immune system because related germline-encoded inhibitory receptors are widely expressed on other immune cells.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Host MHC class Ia molecules alter IFN-γ production and cytotoxic activity of NK subsets.
Figure 2: Licensing of NK cells expressing inhibitory Ly49 receptors specific for self-MHC class I molecules.
Figure 3: Gene transfer of intact Ly49A, but not cytoplasmic domain-deleted (Ly49A cytoΔ ) or ITIM-mutated (Ly49A YtoF ) Ly49A, licenses NK cells in the presence of its ligand.
Figure 4: Licensing is preserved in SHP1-deficient NK cells.
Figure 5: Model for NK cell licensing in the H2-K b+ D d– mouse.

References

  1. 1

    Murase, K. et al. A membrane-anchored protein kinase involved in Brassica self-incompatibility signalling. Science 303, 1516–1519 (2004)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Karlhofer, F. M., Ribaudo, R. K. & Yokoyama, W. M. MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells. Nature 358, 66–70 (1992)

    ADS  CAS  Article  Google Scholar 

  3. 3

    Lanier, L. L. NK cell receptors. Annu. Rev. Immunol. 16, 359–393 (1998)

    CAS  Article  Google Scholar 

  4. 4

    Moretta, L., Biassoni, R., Bottino, C., Mingari, M. C. & Moretta, A. Human NK-cell receptors. Immunol. Today 21, 420–422 (2000)

    CAS  Article  Google Scholar 

  5. 5

    Trowsdale, J. Genetic and functional relationships between MHC and NK receptor genes. Immunity 15, 363–374 (2001)

    CAS  Article  Google Scholar 

  6. 6

    Yokoyama, W. M. & Plougastel, B. F. Immune functions encoded by the natural killer gene complex. Nature Rev. Immunol. 3, 304–316 (2003)

    CAS  Article  Google Scholar 

  7. 7

    Bix, M. et al. Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature 349, 329–331 (1991)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Furukawa, H. et al. Tolerance of NK and LAK activity for HLA class I-deficient targets in a TAP1-deficient patient (bare lymphocyte syndrome type I). Hum. Immunol. 60, 32–40 (1999)

    CAS  Article  Google Scholar 

  9. 9

    Raulet, D. H., Vance, R. E. & McMahon, C. W. Regulation of the natural killer cell receptor repertoire. Annu. Rev. Immunol. 19, 291–330 (2001)

    CAS  Article  Google Scholar 

  10. 10

    Sentman, C. L., Olsson, M. Y. & Karre, K. Missing self recognition by natural killer cells in MHC class I transgenic mice. A ‘receptor calibration’ model for how effector cells adapt to self. Semin. Immunol. 7, 109–119 (1995)

    CAS  Article  Google Scholar 

  11. 11

    Kim, S. et al. In vivo developmental stages in murine natural killer cell maturation. Nature Immunol. 3, 523–528 (2002)

    Article  Google Scholar 

  12. 12

    Hanke, T. et al. Direct assessment of MHC class I binding by seven Ly49 inhibitory NK cell receptors. Immunity 11, 67–77 (1999)

    CAS  Article  Google Scholar 

  13. 13

    Nakamura, M. C. et al. Mouse Ly-49D recognizes H2-Dd and activates natural killer cell cytotoxicity. J. Exp. Med. 189, 493–500 (1999)

    CAS  Article  Google Scholar 

  14. 14

    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 

  15. 15

    Vance, R. E., Kraft, J. R., Altman, J. D., Jensen, P. E. & Raulet, D. H. Mouse CD94/NKG2A is a natural killer cell receptor for the nonclassical major histocompatibility complex (MHC) class I molecule Qa-1(b). J. Exp. Med. 188, 1841–1848 (1998)

    CAS  Article  Google Scholar 

  16. 16

    Lybarger, L. et al. Enhanced immune presentation of a single-chain major histocompatibility complex class I molecule engineered to optimize linkage of a C-terminally extended peptide. J. Biol. Chem. 278, 27105–27111 (2003)

    CAS  Article  Google Scholar 

  17. 17

    Brennan, J., Lemieux, S., Freeman, J. D., Mager, D. L. & Takei, F. Heterogeneity among Ly-49C natural killer (NK) cells—characterization of highly related receptors with differing functions and expression patterns. J. Exp. Med. 184, 2085–2090 (1996)

    CAS  Article  Google Scholar 

  18. 18

    Doucey, M. A. et al. Cis association of Ly49A with MHC class I restricts natural killer cell inhibition. Nature Immunol. 5, 328–336 (2004)

    CAS  Article  Google Scholar 

  19. 19

    Andersson, M. et al. MHC class I mosaic mice reveal insights into control of Ly49C inhibitory receptor expression in NK cells. J. Immunol. 161, 6475–6479 (1998)

    CAS  PubMed  Google Scholar 

  20. 20

    Nakamura, M. C. et al. Mouse Ly-49A interrupts early signalling events in natural killer cell cytotoxicity and functionally associates with the Shp-1 tyrosine phosphatase. J. Exp. Med. 185, 673–684 (1997)

    CAS  Article  Google Scholar 

  21. 21

    Starr, T. K., Jameson, S. C. & Hogquist, K. A. Positive and negative selection of T cells. Annu. Rev. Immunol. 21, 139–176 (2003)

    CAS  Article  Google Scholar 

  22. 22

    Long, E. O. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875–904 (1999)

    CAS  Article  Google Scholar 

  23. 23

    Bennett, M. et al. Hybrid resistance: ‘negative’ and ‘positive’ signalling of murine natural killer cells. Semin. Immunol. 7, 121–127 (1995)

    CAS  Article  Google Scholar 

  24. 24

    Barao, I. & Murphy, W. J. The immunobiology of natural killer cells and bone marrow allograft rejection. Biol. Blood Marrow Transplant. 9, 727–741 (2003)

    CAS  Article  Google Scholar 

  25. 25

    Ruggeri, L. et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295, 2097–2100 (2002)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Parham, P. & McQueen, K. L. Alloreactive killer cells: hindrance and help for haematopoietic transplants. Nature Rev. Immunol. 3, 108–122 (2003)

    CAS  Article  Google Scholar 

  27. 27

    Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999)

    CAS  Article  Google Scholar 

  28. 28

    Yu, Y. Y., Netuschil, N., Lybarger, L., Connolly, J. M. & Hansen, T. H. Cutting edge: single-chain trimers of MHC class I molecules form stable structures that potently stimulate antigen-specific T cells and B cells. J. Immunol. 168, 3145–3149 (2002)

    CAS  Article  Google Scholar 

  29. 29

    Lybarger, L., Wang, X., Harris, M. R.,, Virgin, H. W. & Hansen, T. H. Virus subversion of the MHC class I peptide-loading complex. Immunity 18, 121–130 (2003)

    CAS  Article  Google Scholar 

  30. 30

    Furukawa, H., Iizuka, K., Poursine-Laurent, J., Shastri, N. & Yokoyama, W. M. A ligand for the murine NK activation receptor Ly-49D: activation of tolerized NK cells from β2-microglobulin-deficient mice. J. Immunol. 169, 126–136 (2002)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

Work in the Yokoyama laboratory is supported by the Howard Hughes Medical Institute, the Barnes-Jewish Hospital Foundation and grants from the National Institutes of Health. Transgenic production and genotyping were supported by the Rheumatic Diseases Core Center grant. This study was also supported by an NIH grant to the Hansen laboratory. The authors thank M. Miley and D. Fremont for initial production of the SCT–Kb tetramers, E. Holroyd, J. Mohan, D. Higuchi and R. Rodrigues for technical assistance, and P. Allen, M. Colonna, J. Loh and E. Unanue for critical comments on the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Wayne M. Yokoyama.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure Legends

This file contains figure legends for all six Supplementary Figures. (PDF 79 kb)

Supplementary Figures

Contains Supplementary Figures S1-S6. (PDF 170 kb)

Supplementary Methods

Additional details of methods to accompany those given in the main text. (PDF 36 kb)

Supplementary Notes

This file contains additional references on the study. (PDF 64 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kim, S., Poursine-Laurent, J., Truscott, S. et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436, 709–713 (2005). https://doi.org/10.1038/nature03847

Download citation

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

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