Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells

Vliet, Sandra J. van; Liempt, Ellis van; Saeland, Eiríkur; Aarnoudse, Corlien A.; Appelmelk, Ben J.; Irimura, Tatsuro; Geijtenbeek, Teunis B. H.; Blixt, Ola; Alvarez, Richard A.; Die, Irma van; Kooyk, Yvette van

doi:10.1093/intimm/dxh246

Cited by 202 publications

(229 citation statements)

References 41 publications

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“…Human MGL (hMGL) is a type II C-type lectin, expressed in vitro by macrophages and monocyte derived DCs and in vivo by DCs of skin and lymph nodes [5,6]. Its carbohydrate recognition domains contain a QPD sequence that is responsible for recognition of α-or β-N-acetylgalactosamine (GalNAc, Tn) residues of N-and O-glycans carried by glycoproteins and/or glycosphingolipids [7]. In mice, there are two homologs of hMGL, MGL1 and MGL2 [8], expressed by dermal DCs and alternatively activated macrophages [5,9].…”

Section: Introductionmentioning

confidence: 99%

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

et al. 2012

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Dendritic cells (DCs) sense the microenvironment through several types of receptors recognizing pathogen-associated molecular patterns. In particular, C-type lectins, expressed by distinct subsets of DCs, recognize and internalize specific carbohydrate antigen in a Ca 2+ -dependent manner. Targeting of these receptors is becoming an efficient strategy of delivering antigens in DC-based anticancer immunotherapy. Here we investigated the role of the macrophage galactose type C-lectin receptor (MGL), expressed by immature DCs (iDCs), as a molecular target for α-N-acetylgalactosamine (GalNAc or Tn)-carrying tumor-associated antigens to improve DC performance. MGL expressed by ex vivo-generated iDCs from healthy donors was engaged by a 60-mer MUC1 9Tn -glycopeptide as a Tn-carrying tumor-associated antigen, and an anti-MGL antibody, as a specific MGL binder. We demonstrated that MGL engagement induced homotrimers and homodimers, triggering the phosphorylation of extracellular signal-regulated kinase 1,2 (ERK1,2) and nuclear factor-κB activation. Analysis of DC phenotype and function demonstrated that MGL engagement improved DC performance as antigen-presenting cells, promoting the upregulation of maturation markers, a decrease in phagocytosis, an enhancement of motility, and most importantly an increase in antigen-specific CD8 + T-cell activation. These results demonstrate that the targeting of MGL receptor on human DCs has an adjuvant effect and that this strategy can be used to design novel anticancer vaccines. Keywords: C-type lectins · Dendritic cells · Macrophage galactose-type C-type lectin (MGL) · MUC1 · Tn-tumor associated antigens IntroductionDendritic cells (DCs), as professional antigen-presenting cells (APCs), sense the microenvironment through different types of Correspondence: Prof. Marianna Nuti e-mail: marianna.nuti@uniroma1.it receptors to scan local environmental changes and eliminate incoming pathogens [1]. They play an essential role in the uptake of self-or pathogen-associated antigens, thus, steering and directing the immune response. After activation, DCs migrate to the draining lymph nodes, where they initiate specific immunity * These authors contributed equally to this work. The most important molecules from the CLR family include macrophage galactose type C-lectin (MGL), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), the mannose receptor, DEC205, and Dectin-1. These receptors are able to trigger distinct signaling pathways that modulate DC functions through the expression of specific molecules and cytokines, determining the polarization of T cells [4]. These properties make this C-type lectin family an optimal tool for DC targeting in cancer vaccination. Human MGL (hMGL) is a type II C-type lectin, expressed in vitro by macrophages and monocyte derived DCs and in vivo by DCs of skin and lymph nodes [5,6]. Its carbohydrate recognition domains contain a QPD sequence that is responsible for recognition of α-or β-N-acetylgalactosamine (GalNAc, Tn) res...

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Section: Introductionmentioning

confidence: 99%

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

et al. 2012

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“…MGL-Fc consisting of the extracellular domains of MGL fused to the human IgG1-Fc tail was generated as described previously (15). T cells were stained for 30 min at 37°C with 10 g/ml MGL-Fc or 5 g/ml of the biotinylated lectins in Hanks' buffered saline solution containing 0.5% BSA.…”

Section: Dc-cd4mentioning

confidence: 99%

“…Cosmc-In lymphocytes, O-glycosylation is initiated through the addition of a single GalNAc residue to serine or threonine, thereby forming the Tn antigen, one the major ligands of MGL (15). Normally, this Tn antigen is elongated to the core 1 glycan (Gal␤1-3GalNac) through the action of the glycosyltransferase core 1 ␤3GalT and its chaperone Cosmc (23).…”

Section: Erk-calcineurin Axis Regulates Expression Of the Glycosyltramentioning

confidence: 99%

Human T Cell Activation Results in Extracellular Signal-regulated Kinase (ERK)-Calcineurin-dependent Exposure of Tn Antigen on the Cell Surface and Binding of the Macrophage Galactose-type Lectin (MGL)*

Vliet

Vuist²,

Lenos³

et al. 2013

Journal of Biological Chemistry

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Background: The C-type lectin macrophage galactose-type lectin (MGL) specifically dampens effector T cell function. Results: Activation through the ERK and calcineurin pathways leads to dramatic changes in T cell surface glycosylation. Conclusion: MGL-binding glycans are expressed only on recently activated T cells. Significance: This study provides mechanistic insight into the signaling pathways that regulate T cell surface glycosylation.

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“…Human MGL (Macrophage Galactose type C-type Lectin) is a C-type lectin expressed by immature myeloid Dendritic Cells (iDCs) and macrophages (Ms), able to bind the N-Acetyl-Galactosamine residues (GalNAc or Tn). Any glycolipid, glycoprotein and pathogen carrying GalNAc is recognized and internalized by MGL expressing cells, thus including MGL in the list of Pathogen Recognition Receptors (PRRs) [3].…”

Section: Introductionmentioning

confidence: 99%

Seasonal modulation of the C-type lectin MGL on human DCs

Zizzari¹,

Napoletano²,

Rughetti³

et al. 2013

OJI

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The C-type lectin MGL is a pathogen recognition receptor, expressed by dendritic cells (DCs) and macrophages (Ms), able to bind GalNAc (Tn)-carrying structures. This receptor also recognized Tn-TAAs that were internalized, processed and presented by DCs to T cells and it acted as an adjuvant on DCs, highlighting its possible application in anti-cancer vaccination. In this work, we found that this receptor present a seasonal modulation: its expression is higher in winter rather than in summer. The percentage of MGL + donors displayed a negative trend that dropped to 33% during the summer and increased up to 100% in winter. This modulation could be also ascribed to the circa-annual variation of glucocorticoids, in fact MGL is up-regulated in presence of dexamethasone in vitro. The seasonal variation of this receptor could be an important point in the field of tumor vaccination strategies.

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Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells

Cited by 202 publications

References 41 publications

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

Human T Cell Activation Results in Extracellular Signal-regulated Kinase (ERK)-Calcineurin-dependent Exposure of Tn Antigen on the Cell Surface and Binding of the Macrophage Galactose-type Lectin (MGL)*

Seasonal modulation of the C-type lectin MGL on human DCs

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