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

Daniel M Andrews, Lucy C Sullivan, Nikola Baschuk, Christopher James Chan, Richard Berry, Claire L Cotterell, Jie Lin, Heloise Halse, Sally V Watt, Jennifer Poursine-Laurent, Chyung-Ru Wang, Anthony A Scalzo, Wayne M Yokoyama, Jamie Rossjohn, Andrew G Brooks, Mark J Smyth

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44 Citations (Scopus)


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-2D(d). 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.
Original languageEnglish
Pages (from-to)1171 - 1177
Number of pages7
JournalNature Immunology
Issue number12
Publication statusPublished - 2012

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