Combined TLR2 and TLR4 ligation in the context of bacterial or helminth extracts in human monocyte derived dendritic cells: molecular correlates for Th1/Th2 polarization.
BACKGROUND
Recognition of pathogens by dendritic cells (DCs) through interaction with pattern recognition receptors, including Toll like receptors (TLR), is crucial for the initiation of appropriate polarized T helper (Th) cell responses. Yet, the characteristics and differences in molecular profiles of DCs with different T cell polarizing capacities are still poorly defined. To address this issue, the molecular profile of human monocyte derived DCs was characterized after exposure to TLR4 ligand LPS in combination with the Th1 promoting bacterial extracts from Listeria monocytogenes and Escherichia coli or the Th2 promoting helminth derived phospholipids from Schistosoma mansoni and Ascaris lumbricoides, all with TLR2 activating capacity.


RESULTS
With regard to the signalling pathways activated upon exposure to LPS and the TLR2 activating compounds, we find that the ratio of activated Mitogen Activated Protein Kinases (MAPK) p-ERK/p-p38 is lower in DCs stimulated with the bacterial products compared to DCs stimulated with the helminth products, which correlates with the Th1 and Th2 polarizing capacity of these compounds. Furthermore, analysis of the mRNA expression levels of a set of 25 carefully selected genes potentially involved in modulation of T cell polarization revealed that the mRNA expression of notch ligand delta-4 and transcription factor c-fos are differentially regulated and show a strong correlation with Th1 and Th2 polarization, respectively.


CONCLUSIONS
This study shows that combined TLR2 and TLR4 activation in the context of different antigen sources can induce very distinct molecular profiles in DCs and suggests that the Th1/Th2 polarizing capacity of compounds can be predicted with the molecular signature they induce in DCs.
van Riet
Elly
E
Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands. evanriet@lacdr.leidenuniv.nl
Everts
Bart
B
Retra
Kim
K
Phylipsen
Marion
M
van Hellemond
Jaap J
JJ
Tielens
Aloysius G M
AG
van der Kleij
Desiree
D
Hartgers
Franca C
FC
Yazdanbakhsh
Maria
M
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000947:Antigens, Helminth / Q000276:immunology; D017164:Ascaris lumbricoides / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D004789:Enzyme Activation / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008089:Listeria monocytogenes / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012550:Schistosoma mansoni / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology* / Q000378:metabolism
D000942:Antigens, Bacterial; D000947:Antigens, Helminth; D012333:RNA, Messenger; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D020928:Mitogen-Activated Protein Kinases