Abstract
Upregulation of the inducible gene products MICA (human) and Rae-1 (mouse) may promote tumor surveillance and autoimmunity by engaging the activating receptor NKG2D on natural killer (NK) cells and T cells. Nevertheless, sustained expression of MICA by tumors can also elicit NKG2D downregulation, perhaps indicating 'immunoevasion'. Investigating this paradox, we report here that constitutive Rae-1epsilon transgene expression in normal epithelium elicited local and systemic NKG2D downregulation, generalized but reversible defects in NK cell-mediated cytotoxicity and mild CD8(+) T cell defects. The extent of NKG2D downregulation correlated well with the incidence and progression of cutaneous carcinogenesis, emphasizing the utility of NKG2D as a marker of tumor resistance. Thus, NKG2D engagement is a natural mediator of immunosurveillance, which can be compromised by locally sustained ligand expression but potentially restored by innate immune activation.
Publication types
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Research Support, N.I.H., Extramural
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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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9,10-Dimethyl-1,2-benzanthracene
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Animals
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Carcinoma / etiology
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Carcinoma / metabolism
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Carcinoma / pathology
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Cell Line, Tumor
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Disease Susceptibility
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Down-Regulation
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Female
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Immunologic Surveillance
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Killer Cells, Natural / immunology*
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Ligands
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Male
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Membrane Proteins / biosynthesis
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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, Knockout
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Mice, Transgenic
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NK Cell Lectin-Like Receptor Subfamily K
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Papilloma / etiology
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Papilloma / metabolism
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Papilloma / pathology
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Receptors, Immunologic / immunology*
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Receptors, Immunologic / metabolism*
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Receptors, Natural Killer Cell
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Skin Neoplasms / etiology
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Skin Neoplasms / metabolism
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Skin Neoplasms / pathology
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T-Lymphocytes / immunology
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Tetradecanoylphorbol Acetate
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Tumor Burden
Substances
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KLRK1 protein, human
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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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9,10-Dimethyl-1,2-benzanthracene
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Tetradecanoylphorbol Acetate