Abstract
Human mature dendritic cells (DCs) can efficiently stimulate natural killer (NK)-cell responses without being targeted by their cytotoxicity. To understand this important regulatory crosstalk, we characterized the development of the immunologic synapse between mature DCs and resting NK cells. Conjugates between these 2 innate leukocyte populations formed rapidly, persisted for prolonged time periods and matured with DC-derived f-actin polymerization at the synapse. Polarization of IL-12 and IL-12R to the synapse coincided with f-actin polymerization, while other activating and inhibitory molecules were enriched at the interface between DCs and NK cells earlier. Functional assays revealed that inhibition of f-actin polymerization in mature synapses led to an increase of IFN-γ secretion and cytotoxicity by NK cells. This elevated NK-cell reactivity resulted from decreased inhibitory signaling in the absence of MHC class I polarization at the interface, which was observed on inhibition of f-actin polymerization in DCs. Thus, inhibitory signaling is stabilized by f-actin at the synapse between mature DCs and resting NK cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / immunology
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Actins / metabolism
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Cell Communication / immunology
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Cells, Cultured
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Coculture Techniques
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Cytoskeleton / immunology*
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Cytoskeleton / metabolism
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / ultrastructure
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Flow Cytometry
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Humans
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Immunological Synapses / immunology*
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Immunological Synapses / metabolism
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Interleukin-15 Receptor alpha Subunit / immunology
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Interleukin-15 Receptor alpha Subunit / metabolism
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K562 Cells
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / ultrastructure
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Microscopy, Confocal
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Microscopy, Electron, Transmission
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Microscopy, Fluorescence
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Microtubule-Organizing Center / immunology
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Microtubule-Organizing Center / metabolism
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RNA Interference
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Receptors, Interleukin-12 / immunology
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Receptors, Interleukin-12 / metabolism
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Receptors, KIR / immunology
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Receptors, KIR / metabolism
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Wiskott-Aldrich Syndrome Protein / genetics
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Wiskott-Aldrich Syndrome Protein / immunology
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Wiskott-Aldrich Syndrome Protein / metabolism
Substances
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Actins
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Interleukin-15 Receptor alpha Subunit
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Receptors, Interleukin-12
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Receptors, KIR
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WAS protein, human
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Wiskott-Aldrich Syndrome Protein
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Interleukin-12