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      Mannose–fucose recognition by DC-SIGN

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          Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN). DC-SIGN is a C-type lectin receptor that recognizes N-linked high-mannose oligosaccharides and branched fucosylated structures. It is now clear that the biological role of DC-SIGN is two-fold. It is primarily expressed by dendritic cells and mediates important functions necessary for the induction of successful immune responses that are essential for the clearance of microbial infections, such as the capture, destruction, and presentation of microbial pathogens to induce successful immune responses. Yet, on the other hand, pathogens may also exploit DC-SIGN to modulate DC functioning thereby skewing the immune response and promoting their own survival. This chapter presents an overview of the structure of DC-SIGN and its expression pattern among immune cells. The current state of knowledge of DC-SIGN-carbohydrate interactions is discussed and how these interactions influence dendritic cell functioning is examined. The molecular aspects that underlie the selectivity of DC-SIGN for mannose-and fucose-containing carbohydrates are detailed. Furthermore, the chapter discusses the role of DC-SIGN in dendritic cell biology and how certain bacterial pathogens exploit DC-SIGN to escape immune surveillance.

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          Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses.

          Contact between dendritic cells (DC) and resting T cells is essential to initiate a primary immune response. Here, we demonstrate that ICAM-3 expressed by resting T cells is important in this first contact with DC. We discovered that instead of the common ICAM-3 receptors LFA-1 and alphaDbeta2, a novel DC-specific C-type lectin, DC-SIGN, binds ICAM-3 with high affinity. DC-SIGN, which is abundantly expressed by DC both in vitro and in vivo, mediates transient adhesion with T cells. Since antibodies against DC-SIGN inhibit DC-induced proliferation of resting T cells, our findings predict that DC-SIGN enables T cell receptor engagement by stabilization of the DC-T cell contact zone.
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            Mycobacteria Target DC-SIGN to Suppress Dendritic Cell Function

            Mycobacterium tuberculosis represents a world-wide health risk and immunosuppression is a particular problem in M. tuberculosis infections. Although macrophages are primarily infected, dendritic cells (DCs) are important in inducing cellular immune responses against M. tuberculosis. We hypothesized that DCs represent a target for M. tuberculosis and that the observed immuno-suppression results from modulation of DC functions. We demonstrate that the DC-specific C-type lectin DC-SIGN is an important receptor on DCs that captures and internalizes intact Mycobacterium bovis bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block M. bovis BCG infection of DCs. ManLAM is also secreted by M. tuberculosis–infected macrophages and has been implicated as a virulence factor. Strikingly, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation. Both mycobacteria and LPS induce DC maturation through Toll-like receptor (TLR) signaling, suggesting that DC-SIGN, upon binding of ManLAM, interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the ManLAM-mediated immunosuppressive effects. Our results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Moreover, we demonstrate that DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting that DC-SIGN may represent a molecular target for clinical intervention in infections other than HIV-1.
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              DC-SIGN: escape mechanism for pathogens.

              Dendritic cells (DCs) are crucial in the defence against pathogens. Invading pathogens are recognized by Toll-like receptors (TLRs) and receptors such as C-type lectins expressed on the surface of DCs. However, it is becoming evident that some pathogens, including viruses, such as HIV-1, and non-viral pathogens, such as Mycobacterium tuberculosis, subvert DC functions to escape immune surveillance by targeting the C-type lectin DC-SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin). Notably, these pathogens misuse DC-SIGN by distinct mechanisms that either circumvent antigen processing or alter TLR-mediated signalling, skewing T-cell responses. This implies that adaptation of pathogens to target DC-SIGN might support pathogen survival.
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                Author and article information

                Journal
                Microbial Glycobiology
                Microbial Glycobiology
                22 October 2009
                2010
                22 October 2009
                : 673-695
                Affiliations
                Division of Structural Biochemistry, Department of Immunochemistry and Biochemical Microbiology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany
                Department of Microbiology, Immunology and Pathology, College of Veterinary and Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA
                Institute for Glycomics, Gold Coast Campus, Griffith University, Queensland, Australia
                Article
                B978-0-12-374546-0.00034-1
                10.1016/B978-0-12-374546-0.00034-1
                7150001
                c2ab87c1-56d4-4b5e-a637-dfdb94060ac2
                Copyright © 2010 Elsevier Inc. All rights reserved.

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