Abstract
IL-21 is a recently identified cytokine that stimulates mouse NK cell effector functions in vitro. In this study we demonstrate that IL-21 achieves its stimulatory effect by inducing the development of mature NK cells into a large granular lymphocyte phenotype with heightened effector function. IL-21 treatment results in increased cell size and granularity and a corresponding decrease in cell viability and proliferative potential. These cells up-regulate the expression of the inhibitory CD94-NKG2A receptor complex and the activation markers CD154 and killer cell, lectin-like-receptor G1. Surprisingly, IL-21 treatment also results in down-regulation of the pan-NK marker, NK1.1. Coinciding with these cellular changes IL-21 enhances cytolytic capacity across a spectrum of target sensitivities and induces IL-10 and IFN-gamma production. In vivo treatment with IL-21 results in a very similar activation and phenotypic maturation of NK cells as well as a potent increase in NK cell-mediated anti-tumor immunity that is perforin dependent. These developmental changes suggested that IL-21 functions to induce the terminal differentiation of mouse NK cells, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance.
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 / biosynthesis
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Antigens, Ly
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Antigens, Surface
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Biomarkers / analysis
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Cell Differentiation / immunology
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Cell Line, Tumor
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Cells, Cultured
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Cytokines / biosynthesis
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Cytokines / metabolism
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Cytotoxicity, Immunologic / immunology
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Down-Regulation / immunology
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / physiology
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Immunophenotyping
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Interleukin-15 / physiology
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Interleukin-2 / physiology
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Interleukins / administration & dosage
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Interleukins / physiology*
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Killer Cells, Natural / cytology*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Lectins, C-Type
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Liver Neoplasms / immunology
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Liver Neoplasms / prevention & control
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Liver Neoplasms / secondary
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Lymphocyte Activation / immunology
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Lymphocyte Subsets / immunology
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Lymphocyte Subsets / metabolism
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Melanoma, Experimental / immunology
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Melanoma, Experimental / prevention & control
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Melanoma, Experimental / secondary
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Membrane Glycoproteins / deficiency
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred BALB C
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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 B
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Perforin
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Pore Forming Cytotoxic Proteins
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Protein Biosynthesis
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Proteins / antagonists & inhibitors
Substances
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Antigens
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Antigens, Ly
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Antigens, Surface
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Biomarkers
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Cytokines
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Growth Inhibitors
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Interleukin-15
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Interleukin-2
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Interleukins
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Klrb1c protein, mouse
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Lectins, C-Type
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Membrane Glycoproteins
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NK Cell Lectin-Like Receptor Subfamily B
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Pore Forming Cytotoxic Proteins
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Proteins
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Perforin
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interleukin-21