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

Nature volume 436, pages 709–713 (2005)Cite this article

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.

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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.

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References

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

    Article  ADS  CAS  Google Scholar 

  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)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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. 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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

  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)

    Article  CAS  Google Scholar 

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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.

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Author notes

  1. Lonnie Lybarger

    Present address: Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tuscon, Arizona, 85724, USA

Authors and Affiliations

  1. Rheumatology Division, Departments of Medicine, Howard Hughes Medical Institute,

    Sungjin Kim, Jennifer Poursine-Laurent, Yun-Jeong Song, Liping Yang, Anthony R. French, John B. Sunwoo & Wayne M. Yokoyama

  2. Pathology and Immunology,

    Steven M. Truscott, Lonnie Lybarger, Ted H. Hansen & Wayne M. Yokoyama

  3. Pediatrics,

    Anthony R. French

  4. Otolaryngology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA

    John B. Sunwoo

  5. Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Université du Québec, Laval, H7V 1B7, Québec, Canada

    Suzanne Lemieux

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Correspondence to Wayne M. Yokoyama.

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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

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