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1.
Immunol Lett ; 116(1): 86-94, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-18166232

ABSTRACT

Toll-like receptors (TLRs) play an important role in the innate recognition of pathogens by dendritic cells (DCs) and in the induction of immune responses. Few studies have been devoted to address the impact of TLR2 (a fully MyD88-dependent receptor) and TLR3 (a fully TRIF-dependent receptor) co-activation on DC functions, especially in the mouse system. Using canonical agonists, we show that TLR2 acts in concert with TLR3 to induce the synthesis of inflammatory cytokines (TNF-alpha, IL-6), of some IL-12 family members (IL-12p40, IL-12p23, IL-27p28) and of the Notch ligand Delta-4 by mouse DCs. In contrast, TLR2 interferes with the TLR3-induced expression of type I interferon stimulated genes (MIG/CXCL9, IP-10/CXCL10, GARG39) and IL-12p35. We also report that TLR2 cooperates with TLR3 to enhance the DC-mediated production of IFN-gamma by Natural Killer cells and by conventional Ag-specific T lymphocytes. To conclude, our data support the existence of TLR2 and TLR3 synergy and cross-inhibition in DCs that could be important to strengthen immune responses during infection.


Subject(s)
Dendritic Cells/metabolism , Interleukin-12/metabolism , Receptor Cross-Talk , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 3/metabolism , Animals , Antigens, Differentiation , Cell Differentiation/immunology , Coculture Techniques , Dendritic Cells/cytology , Dendritic Cells/immunology , Epitopes , Flow Cytometry , Gene Expression Regulation/immunology , Immunity, Cellular , Immunophenotyping , Inflammation Mediators/agonists , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-12/antagonists & inhibitors , Interleukin-12/immunology , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Lymphocyte Activation , Mice , Myeloid Cells/cytology , Myeloid Cells/immunology , Myeloid Cells/metabolism , Toll-Like Receptor 2/agonists , Toll-Like Receptor 2/immunology , Toll-Like Receptor 3/agonists , Toll-Like Receptor 3/immunology , Up-Regulation
2.
Microbes Infect ; 9(14-15): 1606-13, 2007.
Article in English | MEDLINE | ID: mdl-18023390

ABSTRACT

Toll-like receptors (TLRs) play an important role in the innate recognition of pathogens by dendritic cells (DCs) and in the induction of immune responses. However, relatively little is known about their functions in innate/acquired responses to complex eukaryotic microorganisms, including helminth parasites. That Schistosoma mansoni eggs activate myeloid DCs through TLR2 and TLR3 has been shown by us and others, but the consequences of this combined activation are still unknown. We show that the engagement of both TLR2 and TLR3 by schistosome eggs is important for the production of inflammatory cytokines and interferon-stimulated genes, such as some chemokines, by DCs. Strikingly, DCs sensitized with ovalbumin in the presence of parasite eggs dramatically reduce the release of Th2-type cytokines by ovalbumin-specific T lymphocytes, an effect that fully depends on TLR3. Finally, although TLR2 and TLR3 have no role in host resistance and in egg-induced granuloma formation in S. mansoni-infected mice, they individually and additionally increase the Th1/Th2 balance of the immune response. Thus, TLR2 and TLR3 sensing is required to shape the immune response during murine schistosomiasis, but is dispensable to control infection and pathology.


Subject(s)
Dendritic Cells/immunology , Schistosoma mansoni/pathogenicity , Schistosomiasis mansoni/immunology , Schistosomiasis mansoni/pathology , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 3/metabolism , Animals , Female , Mice , Mice, Inbred C57BL , Parasite Egg Count , Schistosoma mansoni/immunology , Schistosomiasis mansoni/parasitology , Th1 Cells/immunology , Th2 Cells/immunology
3.
Infect Immun ; 75(11): 5148-57, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17785480

ABSTRACT

Galectin-3 (Gal-3) is a multifunctional beta-galactoside-binding lectin that senses self-derived and microbial glycoconjugates. Although Gal-3 is important in immune reactions and host defense in some experimental models, the function of Gal-3 during helminthic diseases (e.g., schistosomiasis) is still elusive. We show that, compared to wild-type Schistosoma mansoni-infected mice, infected Gal-3-/- mice have a reduced number of T and B lymphocytes in the spleen, develop reduced liver granulomas at 7 weeks (acute phase) and 14 weeks (chronic phase) postinfection, and mount a biased cellular and humoral Th1 response. In an attempt to understand this latter phenomenon, we studied the role of endogenous Gal-3 in dendritic cells (DCs), the most potent antigen-presenting cells, both in vitro and in vivo. Although Gal-3 deficiency in DCs does not impact their differentiation and maturation processes, it greatly influences the strength (but not the nature) of the adaptive immune response that they trigger, suggesting that Gal-3 deficiency in some other cell types may be important during murine schistosomiasis. As a whole, this study implies that Gal-3 is a modulator of the immune/inflammatory responses during helminthic infection and reveals for the first time that Gal-3 expression in DCs is pivotal to control the magnitude of T-lymphocyte priming.


Subject(s)
Dendritic Cells/immunology , Galectin 3/deficiency , Galectin 3/immunology , Schistosoma mansoni/immunology , Schistosomiasis mansoni/immunology , Animals , Antibodies, Protozoan/blood , B-Lymphocytes/immunology , Cytokines/biosynthesis , Female , Granuloma/pathology , Immunoglobulin G/blood , Liver/pathology , Mice , Mice, Knockout , Spleen/immunology , T-Lymphocytes/immunology
4.
J Biol Chem ; 280(1): 277-83, 2005 Jan 07.
Article in English | MEDLINE | ID: mdl-15519998

ABSTRACT

Stimulation of dendritic cells (DCs) by the egg stage of the helminth parasite Schistosoma mansoni activates a signaling pathway resulting in type I interferon (IFN) and IFN-stimulated gene (ISG) expression. Here, we demonstrate that S. mansoni eggs disjointedly activate myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent pathways in DCs. Inflammatory cytokine expression and NF-kappa B activation in DCs from MyD88-deficient mice were impaired, whereas signaling transducer activator of transcription (STAT) 1(Tyr701) phosphorylation and ISG expression were intact in MyD88 or Toll-like receptor (TLR)4-deficient counterparts. Accordingly, we analyzed distinct TLR members for their ability to respond to schistosome eggs and established that TLR3 resulted in the activation of NF-kappa B and the positive regulatory domain III-I site from IFN-beta promoter. Unexpectedly, egg-derived RNA possessed RNase A-resistant and RNase III-sensitive structures capable of triggering TLR3 activation, suggesting the involvement of double-stranded (ds) structures. Moreover, DCs from TLR3-deficient mice displayed a complete loss of signaling transducer activator of transcription 1 phosphorylation and ISG expression in response to egg-derived dsRNA. Finally, TLR3-deficient DCs showed a reduced response to schistosome eggs relative to wild-type cells. Collectively, our data suggest for the first time that dsRNA from a non-viral pathogen may act as an inducer of the innate immune system through TLR3.


Subject(s)
Dendritic Cells/metabolism , Membrane Glycoproteins/metabolism , RNA, Double-Stranded/metabolism , Receptors, Cell Surface/metabolism , Schistosoma/metabolism , Schistosomiasis/metabolism , Animals , Dendritic Cells/immunology , Dendritic Cells/parasitology , Immunity, Innate , Membrane Glycoproteins/immunology , Mice , Phosphorylation , Receptors, Cell Surface/immunology , Schistosoma/genetics , Schistosoma/immunology , Schistosomiasis/immunology , Toll-Like Receptor 3 , Toll-Like Receptor 4 , Toll-Like Receptors
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