Abstract
Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKC(KD)) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKC(KD) NK cells exhibit defective killing of MHC-I-deficient, but otherwise normal, target cells, resulting in defective rejection by NKC(KD) mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC(KD) mice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKC(KD) mice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Ly / genetics
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Antigens, Ly / immunology
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Cell Degranulation / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Line, Tumor
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Gene Silencing / immunology
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Histocompatibility Antigens Class I / genetics*
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Histocompatibility Antigens Class I / immunology*
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Killer Cells, Natural / cytology
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Killer Cells, Natural / immunology*
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Lectins, C-Type / genetics
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Lectins, C-Type / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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NK Cell Lectin-Like Receptor Subfamily A / genetics*
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NK Cell Lectin-Like Receptor Subfamily A / immunology*
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NK Cell Lectin-Like Receptor Subfamily D / genetics
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NK Cell Lectin-Like Receptor Subfamily D / metabolism
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NK Cell Lectin-Like Receptor Subfamily K / genetics
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NK Cell Lectin-Like Receptor Subfamily K / immunology
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Neoplasms / genetics
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Neoplasms / immunology
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology
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Receptors, Immunologic / metabolism
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Transsexualism / genetics
Substances
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Antigens, Ly
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Histocompatibility Antigens Class I
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Klra1 protein, mouse
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Klra17 protein, mouse
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Klra7 protein, mouse
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Klri1 protein, mouse
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Klrk1 protein, mouse
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Lectins, C-Type
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Ly49I antigen
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NK Cell Lectin-Like Receptor Subfamily A
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NK Cell Lectin-Like Receptor Subfamily D
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NK Cell Lectin-Like Receptor Subfamily K
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Receptors, Immunologic