Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells.
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.
Napolitani
Giorgio
G
Institute for Research in Biomedicine, Oncology Institute of Southern Switzerland, CH-6500, Bellinzona, Switzerland. giorgio.napolitani@irb.unisi.ch
Rinaldi
Andrea
A
Bertoni
Francesco
F
Sallusto
Federica
F
Lanzavecchia
Antonio
A
D000818:Animals; D023201:CD40 Ligand / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020411:Oligonucleotide Array Sequence Analysis; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014158:Transcription, Genetic
D016207:Cytokines; D004268:DNA-Binding Proteins; C508840:IL23A protein, human; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma