Abstract
Invariant natural killer T (iNKT) cells are a subset of innate lymphocytes that recognize lipid antigens in the context of CD1d and mediate potent immune regulatory functions via the rapid production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4). We investigated whether diverse Toll-like receptor (TLR) signals in myeloid dendritic cells (DCs) could differentially stimulate iNKT cells. Together with the lipopolysaccharide-detecting receptor TLR4, activation of the nucleic acid sensors TLR7 and TLR9 in DCs were particularly potent in stimulating iNKT cells to produce IFN-gamma, but not IL-4. iNKT cell activation in response to TLR9 stimulation required combined synthesis of type I interferon and de novo production of charged beta-linked glycosphingolipid(s) by DCs. In addition, DCs stimulated via TLR9 activated both iNKT cells and NK cells in vivo and protected mice against B16F10-induced melanoma metastases. These data underline the role of TLR9 in iNKT cell activation and might have relevance to infectious diseases and cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acidic Glycosphingolipids / immunology*
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Acidic Glycosphingolipids / metabolism
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Animals
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Antigens, CD1 / immunology
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Antigens, CD1 / metabolism
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Antigens, CD1d
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Cells, Cultured
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Coculture Techniques
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Female
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Immunotherapy, Adoptive
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Interferon Type I / immunology*
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Interferon Type I / metabolism
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Lymphocyte Activation / immunology*
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Neoplasms, Experimental / immunology
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Neoplasms, Experimental / metabolism
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RNA, Messenger / analysis
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Toll-Like Receptor 7 / immunology
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Toll-Like Receptor 7 / metabolism
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Toll-Like Receptor 9 / immunology*
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Toll-Like Receptor 9 / metabolism
Substances
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Acidic Glycosphingolipids
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Antigens, CD1
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Antigens, CD1d
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Interferon Type I
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Membrane Glycoproteins
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RNA, Messenger
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Tlr7 protein, mouse
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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Interferon-gamma