Abstract
IL-12 and TNF-alpha production by dendritic cells (DCs) is a critical step in the initiation of local inflammation and adaptive immune responses. We show in this study that a small molecule immune response modifier that is a Toll-like receptor 7 (TLR7) agonist induces IL-12 and TNF-alpha production from murine CD11c(+)CD11b(+)CD8(-) DCs, a subset not previously known for this activity. Stimulation of these DCs through TLR7 in vivo induces significant cytokine production even 12 h after initial stimulation, as well as migration of the DC into T cell zones of the lymphoid tissue. In contrast, stimulation through TLR4 and TLR9 induced IL-12 production predominantly from CD8(+) DCs, consistent with previously published data. All TLR stimuli induced the increase in surface expression of the activation markers B7-1, B7-2, and class II in both CD8(+) and CD8(-) DCs, demonstrating that CD8(+) DCs do respond to TLR7-mediated stimuli. To date this is the only known stimuli to induce preferential cytokine production from CD8(-) DCs. Given the efficacy of TLR7 agonists as antiviral agents, the data collectively indicate that stimulation of CD8(-) DCs through TLR7 most likely plays a role in the generation of antiviral immune responses.
MeSH terms
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Aminoquinolines / administration & dosage*
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Animals
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CD11b Antigen / biosynthesis*
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CD11c Antigen / biosynthesis*
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CD8 Antigens / biosynthesis
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Cell Line
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Cell Movement / immunology
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Cytokines / biosynthesis
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DNA-Binding Proteins / agonists
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DNA-Binding Proteins / physiology
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Female
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Humans
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Immunologic Factors / pharmacology*
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Injections, Intravenous
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Interleukin-12 / biosynthesis*
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Membrane Glycoproteins / agonists*
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred C57BL
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Myeloid Cells / drug effects
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Receptors, Cell Surface / agonists*
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Receptors, Cell Surface / physiology
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Spleen / cytology
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Spleen / drug effects
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Spleen / immunology
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Spleen / metabolism
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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Tumor Necrosis Factor-alpha / biosynthesis*
Substances
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4-amino-alpha,alpha,2-trimethyl-1H-imidazo(4,5-c)quinoline-1-ethanol
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Aminoquinolines
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CD11b Antigen
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CD11c Antigen
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CD8 Antigens
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Cytokines
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DNA-Binding Proteins
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Immunologic Factors
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Membrane Glycoproteins
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Receptors, Cell Surface
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TLR9 protein, human
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Tlr7 protein, mouse
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Tlr9 protein, mouse
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Toll-Like Receptor 7
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Toll-Like Receptor 9
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Tumor Necrosis Factor-alpha
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Interleukin-12