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-Glucan As a Novel Ligand for DC-SIGN: Involvement of Mycobacterial Capsular Polysaccharides in Host Immune Modulation1
*Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, The Netherlands;
Centre National de la Recherche Scientifique, Département Mécanismes Moléculaires des Infections Mycobacteriennes, Institut de Pharmacologie et de Biologie Structurale, and Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Université Paul Sabatier (Toulouse III), Toulouse, France;
Biochemical Research Laboratory, Ezaki Glico Co., Ltd, Nishiyodogawa-ku, Osaka, Japan,
Department of Biostructural Science and
¶Department of Maxillofacial Anatomy, Tokyo Medical and Dental University, Tokyo, Japan; and
||Carbohydrate Chemistry Laboratory, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
Mycobacterium tuberculosis possesses a variety of immunomodulatory factors that influence the host immune response. When the bacillus encounters its target cell, the outermost components of its cell envelope are the first to interact. Mycobacteria, including M. tuberculosis, are surrounded by a loosely attached capsule that is mainly composed of proteins and polysaccharides. Although the chemical composition of the capsule is relatively well studied, its biological function is only poorly understood. The aim of this study was to further assess the functional role of the mycobacterial capsule by identifying host receptors that recognize its constituents. We focused on 
-glucan, which is the dominant capsular polysaccharide. Here we demonstrate that M. tuberculosis -glucan is a novel ligand for the C-type lectin DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin). By using related glycogen structures, we show that recognition of -glucans by DC-SIGN is a general feature and that the interaction is mediated by internal glucosyl residues. As for mannose-capped lipoarabinomannan, an abundant mycobacterial cell wall-associated glycolipid, binding of -glucan to DC-SIGN stimulated the production of immunosuppressive IL-10 by LPS-activated monocyte-derived dendritic cells. By using specific inhibitors, we show that this IL-10 induction was DC-SIGN-dependent and also required acetylation of NF-
B. Finally, we demonstrate that purified M. tuberculosis -glucan, in contrast to what has been reported for fungal -glucan, was unable to activate TLR2.
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 funded under the European Union Framework 6 program (ref. 37388): ImmunoVacTB: A new approach for developing a less immunosuppressive tuberculosis vaccine.
2 Address correspondence and reprint requests to Dr. Jeroen Geurtsen, Department of Medical Microbiology and Infection Control, VU University Medical Center, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. E-mail address: jeroen.geurtsen{at}vumc.nl
3 Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guérin; CR3, complement receptor 3; DC, dendritic cell; DC-SIGN, dendritic cell-specific ICAM-3-grabbing nonintegrin; HSA, human serum albumin; ManLAM, mannose-capped lipoarabinomannan; MOI, multiplicity of infection; MR, mannose receptor; NMR, nuclear magnetic resonance.
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