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Toll-like receptors (TLRs) sense microbial products and initiate adaptive immune responses by activating dendritic cells (DCs). As pathogens may contain several TLR agonists, we sought to determine whether different TLRs cooperate in DC activation. In human and mouse DCs, TLR3 and TLR4 potently acted in synergy with TLR7, TLR8 and TLR9 in the induction of a selected set of genes. Synergic TLR stimulation increased production of interleukins 12 and 23 and increased the Delta-4/Jagged-1 ratio, leading to DCs with enhanced and sustained T helper type 1-polarizing capacity. Global gene transcriptional analysis showed that TLR synergy 'boosted' only approximately 1% of the transcripts induced by single TLR agonists. These results identify a 'combinatorial code' by which DCs discriminate pathogens and suggest new strategies for promoting T helper type 1 responses.

Original publication

DOI

10.1038/ni1223

Type

Journal article

Journal

Nat Immunol

Publication Date

08/2005

Volume

6

Pages

769 - 776

Keywords

Animals, CD40 Ligand, Cell Membrane, Cytokines, DNA-Binding Proteins, Dendritic Cells, Dose-Response Relationship, Drug, Gene Expression Regulation, Humans, Immunoblotting, Interferon-gamma, Interleukin-12, Interleukin-23, Interleukin-23 Subunit p19, Interleukins, Kinetics, Membrane Glycoproteins, Mice, Mice, Inbred BALB C, Oligonucleotide Array Sequence Analysis, Protein Subunits, RNA, Messenger, Receptors, Cell Surface, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Th1 Cells, Time Factors, Toll-Like Receptor 3, Toll-Like Receptor 4, Toll-Like Receptor 7, Toll-Like Receptor 8, Toll-Like Receptor 9, Toll-Like Receptors, Transcription, Genetic