Abstract
Dendritic cells (DC) regulate NK cell functions, but the signals required for the DC-mediated NK cell activation, i.e., DC-activated NK cell (DAK) activity, remain poorly understood. Upon acute inflammation mimicked by LPS or TNF-alpha, DC undergo a maturation process allowing T and NK cell activation in vitro. Chronic inflammation is controlled in part by Th2 cytokines. In this study, we show that IL-4 selectively confers to DC NK but not T cell stimulatory capacity. IL-4 is mandatory for mouse bone marrow-derived DC grown in GM-CSF (DC(GM/IL-4)) to promote NK cell activation in the draining lymph nodes. IL-4-mediated DAK activity depends on the KARAP/DAP12-triggering receptor expressed on myeloid cell 2 signaling pathway because: 1) gene targeting of the adaptor molecule KARAP/DAP12, a transmembrane polypeptide with an intracytoplasmic immunoreceptor tyrosine-based activation motif, suppresses the DC(GM/IL-4) capacity to activate NK cells, and 2) IL-4-mediated DAK activity is significantly blocked by soluble triggering receptor expressed on myeloid cell 2 Fc molecules. These data outline a novel role for Th2 cytokines in the regulation of innate immune responses through triggering receptors expressed on myeloid cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport / biosynthesis
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Adaptor Proteins, Vesicular Transport / physiology*
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Adoptive Transfer
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Animals
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Cell Communication / genetics
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Cell Communication / immunology
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Cells, Cultured
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Coculture Techniques
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Cytotoxicity, Immunologic / genetics
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Cytotoxicity, Immunologic / immunology*
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / transplantation
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Female
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Inflammation / genetics
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Inflammation / immunology
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Interleukin-4 / physiology*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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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, Nude
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Mice, SCID
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Receptors, Immunologic / biosynthesis
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology*
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Lipopolysaccharides
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Membrane Glycoproteins
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Receptors, Immunologic
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Trem2 protein, mouse
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Tumor Necrosis Factor-alpha
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Tyrobp protein, mouse
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Interleukin-4