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* Immunobiology Section, Laboratory of Parasitic Diseases and
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Division of Immunology, Department of Microbiology and Parasitology, Federal University of Santa Catarina, Florianopolis, Brazil;
Department of Surgery, James H. Quillen College of Medicine, Johnson City, TN 37614; and
¶ Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch, South Africa
Dectin-1 is a fungal pattern recognition receptor that binds to 
-glucans and triggers cytokine production by facilitating interaction with TLR2 or by directly activating spleen tyrosine kinase (Syk). To assess the possible role of Dectin-1 in the innate response to mycobacteria, we used an in vitro system in which IL-12p40 production is measured in splenic dendritic cells (SpDC) following exposure to live Mycobacterium tuberculosis bacilli. Treatment of SpDC with laminarin or glucan phosphate, two molecules known to block Dectin-1-dependent activity, led to a reduction in M. tuberculosis-induced IL-12p40 as well as IL-12p70 production. Moreover, SpDC from Dectin-1–/– chimeric mice displayed reduced IL-12p40 production in response to mycobacteria when compared with Dectin-sufficient DC. Laminarin treatment also inhibited mycobacterial-induced IL-12p40 production in DC from TLR2–/– mice, arguing that Dectin-1 functions independently of TLR2 signaling in this system. Importantly, a Dectin-1 fusion protein was found to directly bind to live mycobacteria in a laminarin-inhibitable manner indicating the presence of ligands for the receptor in the bacterium and laminarin pretreatment resulted in reduced association of mycobacteria to SpDC. In additional experiments, mycobacterial stimulation was shown to be associated with increased phosphorylation of Syk and this response was inhibited by laminarin. Furthermore, pharmacologic inhibition of Syk reduced the M. tuberculosis-induced IL-12p40 response. Together, these findings support a role for Dectin-1 in promoting M. tuberculosis-induced IL-12p40 production by DC in which the receptor augments bacterial-host cell interaction and enhances the subsequent cytokine response through an unknown mechanism involving Syk signaling.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.
2 Address correspondence and reprint requests to Dr. Antonio Gigliotti Rothfuchs, Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Room 6148, Building 50, 50 South Drive, Bethesda, MD 20892-8003. E-mail address: rothfuchsa{at}niaid.nih.gov
3 Abbreviations used in this paper: DC, dendritic cell; PRR, pattern recognition receptor; CLR, C-type lectin receptor; BCG, bacillus Calmette-Guérin; Syk, spleen tyrosine kinase; WT, wild type; SpDC, splenic DC; SpLOD, splenic low density; PEC, peritoneal exudate cell; BMDC, bone marrow-derived DC; MOI, multiplicity of infection; STAg, soluble tachyzoite Ag; CR, complement receptor.
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