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Recognition of the nonclassical MHC class I molecule H2-M3 by the receptor Ly49A regulates the licensing and activation of NK cells

Nature Immunology volume 13, pages 1171–1177 (2012)Cite this article

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An Erratum to this article was published on 19 March 2013

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Abstract

The development and function of natural killer (NK) cells is regulated by the interaction of inhibitory receptors of the Ly49 family with distinct peptide-laden major histocompatibility complex (MHC) class I molecules, although whether the Ly49 family is able bind to other MHC class I–like molecules is unclear. Here we found that the prototypic inhibitory receptor Ly49A bound the highly conserved nonclassical MHC class I molecule H2-M3 with an affinity similar to its affinity for H-2Dd. The specific recognition of H2-M3 by Ly49A regulated the 'licensing' of NK cells and mediated 'missing-self' recognition of H2-M3-deficient bone marrow. Host peptide–H2-M3 was required for optimal NK cell activity against experimental metastases and carcinogenesis. Thus, nonclassical MHC class I molecules can act as cognate ligands for Ly49 molecules. Our results provide insight into the various mechanisms that lead to NK cell tolerance.

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Figure 1: H2-M3 is recognized by C57BL/6 Ly49A.
Figure 2: Ly49A binds with similar affinity to H2-M3 and to H-2Dd.
Figure 3: H2-M3 is not required for NK cell homeostasis.
Figure 4: H2-M3 is required for the control of B16-F10 metastases and MCA-induced fibrosarcoma by NK cells.
Figure 5: Ly49A+ NK cells from H2-M3-deficient mice are not fully licensed.
Figure 6: Rejection of H2-M3-deficient bone marrow demonstrates missing-self recognition.

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  • 19 November 2012

    In the version of this article initially published, two designations for major histocompatibility complex molecules in the second subsection of Results are incorrect. The correct text should read "The affinity of AGPARAAAL-loaded H-2Dd for Ly49A (2.05 ± 0.07 μM; Fig. 2c) was similar to published values36. In contrast, we observed no interaction between Ly49A and SIINFEKL-loaded H-2Kb (Fig. 2d)...." The error has been corrected for HTML and PDF versions of this article.

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Acknowledgements

We thank C. Paget for critical analysis of the manuscript; E. Hawkins, Q. Mundrea, B. Venville, N. McLaughlin and J. Sharkey for technical assistance; and B. Murphy (UC Davis Cancer Center) for the YE1/32 antibody to Ly49A. Supported by the National Health and Medical Research Council of Australia (D.M.A., L.C.S., R.B., M.J.S., A.G.B. and J.R.), Cancer Australia, the Cure Cancer Australia Foundation, the US National Institutes of Health (AI040310 to C.-R.W.) and the Howard Hughes Medical Institute (W.M.Y.).

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Author notes

  1. Lucy C Sullivan, Nikola Baschuk, Andrew G Brooks and Mark J Smyth: These authors contributed equally to this work.

  2. mark.smyth@petermac.org

Authors and Affiliations

  1. Cancer Immunology Program, Trescowthick Laboratories, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Australia

    Daniel M Andrews, Nikola Baschuk, Christopher J Chan, Claire L Cotterell, Heloise Halse, Sally V Watt & Mark J Smyth

  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia

    Daniel M Andrews, Nikola Baschuk, Claire L Cotterell, Heloise Halse, Sally V Watt & Mark J Smyth

  3. Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia

    Lucy C Sullivan, Jie Lin & Andrew G Brooks

  4. Department of Pathology and Immunology, Monash University, Prahran, Australia

    Christopher J Chan & Mark J Smyth

  5. Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Australia

    Richard Berry & Jamie Rossjohn

  6. Rheumatology Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

    Jennifer Poursine-Laurent & Wayne M Yokoyama

  7. Department of Microbiology and Immunology, Northwestern University, Chicago, Illinois, USA

    Chyung-Ru Wang

  8. Centre for Ophthalmology and Vision Science, University of Western Australia, Crawley, Australia

    Anthony A Scalzo

  9. Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Australia

    Anthony A Scalzo

  10. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri, USA

    Wayne M Yokoyama

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Contributions

D.M.A. conceived of, designed and did the experiments with assistance from L.C.S., N.B., C.J.C., R.B., C.L.C., H.H., J.L., S.V.W., J.P.-L. and M.J.S.; C.-R.W., A.A.S., W.M.Y., J.R., A.G.B. and M.J.S. provided reagents and critical input to the analysis of results; and D.M.A., L.C.S., J.R., A.G.B. and M.J.S. wrote the manuscript.

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Correspondence to Daniel M Andrews or Mark J Smyth.

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Andrews, D., Sullivan, L., Baschuk, N. et al. Recognition of the nonclassical MHC class I molecule H2-M3 by the receptor Ly49A regulates the licensing and activation of NK cells. Nat Immunol 13, 1171–1177 (2012). https://doi.org/10.1038/ni.2468

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