The carbohydrate recognition domain of Langerin reveals high structural similarity with the one of DC-SIGN but an additional, calcium-independent sugar-binding site

Chatwell, Lorenz; Holla, Andrea; Kaufer, Benedikt B.; Skerra, Arne

doi:10.1016/j.molimm.2007.10.030

Cited by 56 publications

(89 citation statements)

References 65 publications

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Section: Discussionsupporting

confidence: 62%

“…The MV envelope glycoproteins F and H contain high mannose structures [35] that are likely recognized by Langerin, similarly as shown for C-type lectin DC- SIGN [24]. This is further supported by the high similarity between the folding of the carbohydratebinding domain of Langerin and DC-SIGN [36].The fate of pathogens interacting with Langerin on LCs is not clear. Langerin recycles between the plasma membrane and early endosomes and is associated with Birbeck granules [6].…”

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confidence: 70%

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Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

et al. 2011

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Langerhans cells (LCs) are a subset of DCs that reside in the upper respiratory tract and are ideally suited to sense respiratory virus infections. Measles virus (MV) is a highly infectious lymphotropic and myelotropic virus that enters the host via the respiratory tract. Here, we show that human primary LCs are capable of capturing MV through the C-type lectin Langerin. Both immature and mature LCs presented MV-derived antigens in the context of HLA class II to MV-specific CD4 1 T cells. Immature LCs were not susceptible to productive infection by MV and did not present endogenous viral antigens in the context of HLA class I. In contrast, mature LCs could be infected by MV and presented de novo synthesized viral antigens to MV-specific CD8 1 T cells. Notably, neither immature nor mature LCs were able to cross-present exogenous UV-inactivated MV or MV-infected apoptotic cells. The lack of direct infection of immature LCs, and the inability of both immature and mature LCs to crosspresent MV antigens, suggest that human LCs may not be directly involved in priming MV-specific CD8 1 T cells. Immune activation of LCs seems a prerequisite for MV infection of LCs and subsequent CD8 1 T-cell priming via the endogenous antigen presentation pathway. Eur. J. Immunol. 2011. 41: 2619-2631 DOI 10.1002 Immunity to infection 2619 molecules, a process referred to as cross-presentation which is thought to be important in both viral and tumor immunity [2,3]. It is becoming evident that different DC subsets have specialized functions in anti-viral immunity, e.g. by inducing preferentially CD4 1 or CD8 1 T-cell responses or by inducing innate immunity against pathogens [4,5]. Langerhans cells (LCs) are a subset of DCs that are, in humans, characterized by expression of CD1a, the C-type lectin Langerin and the presence of Birbeck granules [6]. LCs reside in the epidermis and stratified epithelial tissues [7][8][9]. Recently, we have shown that LCs form a barrier against HIV-1; LCs capture HIV-1 through Langerin, resulting in internalization of HIV-1 into Birbeck granules and preventing subsequent HIV-1 transmission [10]. However, little is known about the role of human LCs and Langerin in antigen presentation.Capture of exogenous antigens by LCs leads to induction of CD4 1 T-cell responses [11][12][13]. However, the ability of LCs to cross-present exogenous antigens to CD8 1 T cells has been debated [14][15][16][17]. Klechevsky et al. [13] have shown that in vitrogenerated human LCs from either CD34 1 cells or monocytes are capable of cross-presenting influenza-virus proteins to CD8 1 T cells. However, these in vitro-generated LCs might be different from primary immature LCs.Here, we have investigated the antigen capture and presentation capacity of human primary LCs during measles virus (MV) infection. MV is the causative agent of measles, which remains an important cause of morbidity and mortality in developing countries. MV is a lymphotropic and myelotropic virus and DCs have been implicated in its transmission [18,19]. MV is on...

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Section: Discussionsupporting

confidence: 62%

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confidence: 70%

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

et al. 2011

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“…CRDs 1-3 and 6 -8), or both. This dual binding ability is not unique to MR as a Ca 2ϩ -independent binding site with weak maltose binding affinity has also been identified on Langerin CRD in addition to the Ca 2ϩ -dependent site (40). It is also possible that MR oligomerization may be a Ca 2ϩ -dependent event and under normal circumstances the presence of Ca 2ϩ would allow oligomerization to occur and hence facilitate gp120 binding.…”

Section: Discussionmentioning

confidence: 87%

Oligomerization of the Macrophage Mannose Receptor Enhances gp120-mediated Binding of HIV-1

Lai

Bernhard

Turville

et al. 2009

Journal of Biological Chemistry

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C-type lectin receptors expressed on the surface of dendritic cells and macrophages are able to bind glycoproteins of microbial pathogens via mannose, fucose, and N-acetylglucosamine. Langerin on Langerhans cells, dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin on dendritic cells, and mannose receptor (MR) on dendritic cells and macrophages bind the human immunodeficiency virus (HIV) envelope protein gp120 principally via high mannose oligosaccharides. These C-type lectin receptors can also oligomerize to facilitate enhanced ligand binding. This study examined the effect of oligomerization of MR on its ability to bind to mannan, monomeric gp120, native trimeric gp140, and HIV type 1 BaL. Mass spectrometry analysis of crosslinked MR showed homodimerization on the surface of primary monocyte-derived dendritic cells and macrophages. Both monomeric and dimeric MR were precipitated by mannan, but only the dimeric form was co-immunoprecipitated by gp120. These results were confirmed independently by flow cytometry analysis of soluble monomeric and trimeric HIV envelope and a cellular HIV virion capture assay. As expected, mannan bound to the carbohydrate recognition domains of MR dimers mostly in a calcium-dependent fashion. Unexpectedly, gp120-mediated binding of HIV to dimers on MR-transfected Rat-6 cells and macrophages was not calcium-dependent, was only partially blocked by mannan, and was also partially inhibited by N-acetylgalactosamine 4-sulfate. Thus gp120-mediated HIV binding occurs via the calcium-dependent, non-calcium-dependent carbohydrate recognition domains and the cysteine-rich domain at the C terminus of MR dimers, presenting a much broader target for potential inhibitors of gp120-MR binding.

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“…When designing an efficient HIV-1 entry inhibitor based on C-type lectin antagonism, an agent of choice should bind to both DC-SIGN and mannose receptors, while having no or marginal affinity to Langerin. Although all three receptors bind to virtually the same ligands, selectivity against Langerin is an achievable objective since Langerin binding sites differ from that of DC-SIGN [55]. As expected, selectivity versus Langerin does not necessarily rely on the "core monosaccharide" involved in the binding process, but on spatial constraints formed by adjacent glycan monosaccharide units [56].…”

Section: How Does Dc-sign Choose Among Terminal Monosaccharides?mentioning

confidence: 76%

DC-SIGN Antagonists – A Paradigm of C-Type Lectin Binding Inhibition

Anderluh¹

2012

Carbohydrates - Comprehensive Studies on Glycobiology and Glycotechnology

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The carbohydrate recognition domain of Langerin reveals high structural similarity with the one of DC-SIGN but an additional, calcium-independent sugar-binding site

Cited by 56 publications

References 65 publications

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

Oligomerization of the Macrophage Mannose Receptor Enhances gp120-mediated Binding of HIV-1

DC-SIGN Antagonists – A Paradigm of C-Type Lectin Binding Inhibition

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The carbohydrate recognition domain of Langerin reveals high structural similarity with the one of DC-SIGN but an additional, calcium-independent sugar-binding site

Cited by 56 publications

References 65 publications

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4+ T cells but are incapable of cross‐presentation

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4+ T cells but are incapable of cross‐presentation

Oligomerization of the Macrophage Mannose Receptor Enhances gp120-mediated Binding of HIV-1

DC-SIGN Antagonists – A Paradigm of C-Type Lectin Binding Inhibition

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Product

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Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation

Human Langerhans cells capture measles virus through Langerin and present viral antigens to CD4⁺ T cells but are incapable of cross‐presentation