Abstract
Nonobese diabetic (NOD) mice, a model of insulin-dependent diabetes mellitus, have a defect in natural killer (NK) cell-mediated functions. Here we show impairment in an activating receptor, NKG2D, in NOD NK cells. While resting NK cells from C57BL/6 and NOD mice expressed equivalent levels of NKG2D, upon activation NOD NK cells but not C57BL/6 NK cells expressed NKG2D ligands, which resulted in downmodulation of the receptor. NKG2D-dependent cytotoxicity and cytokine production were decreased because of receptor modulation, accounting for the dysfunction. Modulation of NKG2D was mostly dependent on the YxxM motif of DAP10, the NKG2D-associated adaptor that activates phosphoinositide 3 kinase. These results suggest that NK cells may be desensitized by exposure to NKG2D ligands.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Coculture Techniques
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Cytotoxicity, Immunologic
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Diabetes Mellitus, Type 1 / immunology*
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Enzyme Activation
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Female
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Interferon-gamma / biosynthesis
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Killer Cells, Natural / immunology*
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Ligands
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Lymphocyte Activation
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Male
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Inbred NOD
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NK Cell Lectin-Like Receptor Subfamily K
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Phosphatidylinositol 3-Kinases / metabolism
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism*
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Receptors, Natural Killer Cell
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Transfection
Substances
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Hcst protein, mouse
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Klrk1 protein, mouse
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Ligands
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Membrane Proteins
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NK Cell Lectin-Like Receptor Subfamily K
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Raet1a protein, mouse
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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Interferon-gamma
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Phosphatidylinositol 3-Kinases