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1.  TLR3 and Rig-Like Receptor on Myeloid Dendritic Cells and Rig-Like Receptor on Human NK Cells Are Both Mandatory for Production of IFN-γ in Response to Double-Stranded RNA 
Cross-talk between NK cells and dendritic cells (DCs) is critical for the potent therapeutic response to dsRNA, but the receptors involved remained controversial. We show in this paper that two dsRNAs, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acid [poly(I:C)], similarly engaged human TLR3, whereas only poly(I:C) triggered human RIG-I and MDA5. Both dsRNA enhanced NK cell activation within PBMCs but only poly(I:C) induced IFN-γ. Although myeloid DCs (mDCs) were required for NK cell activation, induction of cytolytic potential and IFN-γ production did not require contact with mDCs but was dependent on type I IFN and IL-12, respectively. Poly(I:C) but not polyadenylic-polyuridylic acid synergized with mDC-derived IL-12 for IFN-γ production by acting directly on NK cells. Finally, the requirement of both TLR3 and Rig-like receptor (RLR) on mDCs and RLRs but not TLR3 on NK cells for IFN-γ production was demonstrated using TLR3- and Cardif-deficient mice and human RIG-I–specific activator. Thus, we report the requirement of cotriggering TLR3 and RLR on mDCs and RLRs on NK cells for a pathogen product to induce potent innate cell activation.
doi:10.4049/jimmunol.1000532
PMCID: PMC3545654  PMID: 20639488
2.  Sex Bias in Susceptibility to MCMV Infection: Implication of TLR9 
PLoS ONE  2012;7(9):e45171.
Toll-like receptor (TLR)-dependent pathways control the activation of various immune cells and the production of cytokines and chemokines that are important in innate immune control of viruses, including mouse cytomegalovirus (MCMV). Here we report that upon MCMV infection wild-type and TLR7−/− male mice were more resistant than their female counterparts, while TLR9−/− male and female mice showed similar susceptibility. Interestingly, 36 h upon MCMV infection TLR9 mRNA expression was higher in male than in female mouse spleens. MCMV infection led to stronger reduction of marginal zone (MZ) B cells, and higher infiltration of plasmacytoid dendritic cells and neutrophils in wild-type male than female mice, while no such sex differences were observed in TLR9−/− mice. In accordance, the serum levels of KC and MIP-2, major neutrophil chemoattractants, were higher in wild-type, but not in TLR9−/−, male versus female mice. Wild-type MCMV-infected female mice showed more severe liver inflammation, necrosis and steatosis compared to infected male mice. Our data demonstrate sex differences in susceptibility to MCMV infection, accompanied by a lower activation of the innate immune system in female mice, and can be attributed, at least in a certain degree, to the lower expression of TLR9 in female than male mice.
doi:10.1371/journal.pone.0045171
PMCID: PMC3447886  PMID: 23028824
3.  TLR8 deficiency leads to autoimmunity in mice 
The Journal of Clinical Investigation  2010;120(10):3651-3662.
TLRs play an essential role in the induction of immune responses by detecting conserved molecular products of microorganisms. However, the function of TLR8 is largely unknown. In the current study, we investigated the role of TLR8 signaling in immunity in mice. We found that Tlr8–/– DCs overexpressed TLR7, were hyperresponsive to various TLR7 ligands, and showed stronger and faster NF-κB activation upon stimulation with the TLR7 ligand R848. Tlr8–/– mice showed splenomegaly, defective development of marginal zone (MZ) and B1 B cells, and increased serum levels of IgM and IgG2a. Furthermore, Tlr8–/– mice exhibited increased serum levels of autoantibodies against small nuclear ribonucleoproteins, ribonucleoprotein, and dsDNA and developed glomerulonephritis, whereas neither Tlr7–/– nor Tlr8–/–Tlr7–/– mice showed any of the phenotypes observed in Tlr8–/– mice. These data provide evidence for a pivotal role for mouse TLR8 in the regulation of mouse TLR7 expression and prevention of spontaneous autoimmunity.
doi:10.1172/JCI42081
PMCID: PMC2947223  PMID: 20811154
4.  Brucella Control of Dendritic Cell Maturation Is Dependent on the TIR-Containing Protein Btp1 
PLoS Pathogens  2008;4(2):e21.
Brucella is an intracellular pathogen able to persist for long periods of time within the host and establish a chronic disease. We show that soon after Brucella inoculation in intestinal loops, dendritic cells from ileal Peyer's patches become infected and constitute a cell target for this pathogen. In vitro, we found that Brucella replicates within dendritic cells and hinders their functional activation. In addition, we identified a new Brucella protein Btp1, which down-modulates maturation of infected dendritic cells by interfering with the TLR2 signaling pathway. These results show that intracellular Brucella is able to control dendritic cell function, which may have important consequences in the development of chronic brucellosis.
Author Summary
A key determinant for intracellular pathogenic bacteria to induce infectious diseases is their ability to avoid recognition by the host immune system. Although most microorganisms internalized by host cells are efficiently cleared, Brucella behave as a Trojan horse causing a zoonosis called brucellosis that affects both humans and animals. Here we show that pathogenic Brucella are able to target host cell defense mechanisms by controlling the function of the sentinels of the immune system, the dendritic cells. In particular, the Brucella TIR-containing protein (Btp1) targets the Toll-like receptor 2 activation pathway, which is a major host response system involved in bacterial recognition. Btp1 is involved in the inhibition of dendritic cell maturation. The direct consequence is a control of inflammatory cytokine secretion and antigen presentation to T lymphocytes. These bacterial proteins are not specific for Brucella and have been identified in other pathogens and may be part of a general virulence mechanism used by several intracellular pathogens to induce disease.
doi:10.1371/journal.ppat.0040021
PMCID: PMC2233671  PMID: 18266466

Results 1-4 (4)