The Macrophage Galactose-Type C-Type Lectin (MGL) Modulates Regulatory T Cell Functions

Zizzari, Ilaria Grazia; Martufi, Paola; Battisti, Federico; Rahimi, Hassan; Caponnetto, S; Bellati, Filippo; Nuti, Marianna; Rughetti, Aurelia; Napoletano, Chiara

doi:10.1371/journal.pone.0132617

Cited by 19 publications

(13 citation statements)

References 26 publications

(31 reference statements)

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“…Human MGL is equipped with a partial dileucine zipper, with YENF internalization motifs [ 25 ], and is involved in (a) the recognition of a large plethora of pathogens by DCs [ 26 , 27 ], (b) in the maintenance of homeostasis [ 28 ], and (c) in the interaction with TAA derived from aberrant glycosylation processes [ 16 , 29 ]. More recently, our group has also demonstrated the role of MGL in immunosuppression given by its capacity to modulate regulatory T cell function [ 30 ] ( Figure 2 ). Thus MGL acts as promiscuous receptor that can bind more than one ligand modulating various types of immune response.…”

Section: Human Mgl In Immune Responsementioning

confidence: 99%

“…We have more recently demonstrated that also CD45RA + Treg subpopulation is affected by MGL engagement. CD45RA-MGL cross-linking induces a decrease of Treg immunosuppressive activity by affecting CD45RA and TCR signaling and an increase of Foxp3 methylation accompanied by a reduced production of suppressive cytokines [ 30 ]. Recent evidence indicates that human MGL expressed on DCs is also able to generate antigen specific IL-10 producing CD4 + T cells when stimulated with foreign and self-antigens fused to an anti-MGL antibody [ 44 ].…”

Section: Human Mgl In Immune Responsementioning

confidence: 99%

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MGL Receptor and Immunity: When the Ligand Can Make the Difference

Zizzari

Napoletano

Battisti

et al. 2015

Journal of Immunology Research

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C-type lectin receptors (CLRs) on antigen-presenting cells (APCs) facilitate uptake of carbohydrate antigens for antigen presentation, modulating the immune response in infection, homeostasis, autoimmunity, allergy, and cancer. In this review, we focus on the role of the macrophage galactose type C-type lectin (MGL) in the immune response against self-antigens, pathogens, and tumor associated antigens (TAA). MGL is a CLR exclusively expressed by dendritic cells (DCs) and activated macrophages (MØs), able to recognize terminal GalNAc residues, including the sialylated and nonsialylated Tn antigens. We discuss the effects on DC function induced throughout the engagement of MGL, highlighting the importance of the antigen structure in the modulation of immune response. Indeed modifying Tn-density, the length, and steric structure of the Tn-antigens can result in generating immunogens that can efficiently bind to MGL, strongly activate DCs, mimic the effects of a danger signal, and achieve an efficient presentation in HLA classes I and II compartments.

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Section: Human Mgl In Immune Responsementioning

confidence: 99%

Section: Human Mgl In Immune Responsementioning

confidence: 99%

MGL Receptor and Immunity: When the Ligand Can Make the Difference

Zizzari

Napoletano

Battisti

et al. 2015

Journal of Immunology Research

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“…Our results improve, at a molecular level, knowledge of the interaction between human CTLs and bacterial glycans and may help to better understand the role of MGL in shaping immunity upon bacterial recognition. MGL has already been reported as a good candidate receptor for DC‐based cancer immunotherapy, given its well‐known ability to endocytose specific tumour‐related antigens . The discovery of the ability of MGL to detect an endotoxin component, LOS, of the outer membrane of the Gram‐negative bacterium E. coli might offer great potential for the future development of therapeutics for bacterial disease intervention.…”

Section: Figurementioning

confidence: 99%

Human Macrophage Galactose‐Type Lectin (MGL) Recognizes the Outer Core of Escherichia coli Lipooligosaccharide

et al. 2019

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Carbohydrate-lectin interactions intervene in and mediate most biological processes, including ac rucial modulation of immune responsest op athogens. Despite growing interesti n investigating the association between host receptorl ectins and exogenous glycanl igands, the molecular mechanisms underlying bacterial recognition by human lectins are still not fully understood.H erein, an ovel molecular interaction between the human macrophage galactose-type lectin (MGL) and the lipooligosaccharide (LOS) of Escherichia coli strain R1 is described. Saturation transfer difference NMR spectroscopy analysis, supportedb yc omputational studies, demonstrated that MGL bound to the purified deacylated LOS R1 mainly throughr ecognition of its outer core and established crucial interactions with the terminal Gala(1,2)Gal epitope. These results assess the ability of MGL to recognise glycan moieties exposed on Gram-negative bacterial surfaces.Bacterialc ell surfaces are decorated with highly diverseg lycoconjugates,i nt he form of capsular polysaccharides, peptidoglycans, lipopolysaccharides( LPSs) and other glycolipids, [1] which perform severalf unctions, ranging from structural to protective roles. [2] Bacterial glycans take part in many keyb iological events, including pathogen recognition,receptor activation, cell adhesion and signal transduction. Additionally,t hese structures often serve as molecular patterns that are recognised by specific glycan-binding receptors of the host immune system,t hus triggeringapathogen-specific immune response.It is well known that LPSs, the major constituents of the outer membrane of Gram-negative bacteria, [3] are one of the main virulence factorsofseveral feared bacterialstrains,including enteropathogenic Escherichia coli,w hich is implicated in severe foodborne and urinary tract infections. [4] From as tructural point of view,L PS is composed of three structural motifs that can be distinguishedb ecause they are encoded by different gene clusters. Lipid A, which represents the glycolipid portion, is an acylated bis-phosphorylated glucosamined isaccharide that anchors the LPS to the outer membrane. Lipid Ai sc ovalentlyl inked to ac ore oligosaccharide (OS) that can be further divided into two different portions: the more conserved inner region, which is characterised by the presence of peculiar sugar residues,s uch as 3-deoxy-d-manno-oct-2-ulopyranosonic acid (KDO),a nd the more variableo uter core. Finally,t he O-antigen, which is ap olysaccharide composed of severalO S repeating units, extends to the extracellularm edium and acts as ah ydrophilic coating surface. [3,5] However,G ram-negative bacteria can also produce rough-typeL PS, namely,l ipooligosaccharide (LOS);atruncated version of LPS that lacks the Oantigen.To date, the receptor complex formed by the toll-like receptor 4a nd the small secreted MD2 protein is among the main speciesi nvolved in bacterial LPS recognition by host immune cells. [6] More recently,i th as been shown that LPSs are also intracellularly detected by caspases...

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“…C-type lectin receptors (CLRs), such as the macrophage galactose N-acetylgalactosamine specific lectin 2 (MGL2, CD301b) have been investigated for their potential to influence immune responses [28][29][30][31][32]. The major ligand for MGL2 is the Tn glycan, and reports suggest the Tn glycan has direct positive influence on antigen uptake mediated in an MGL2 dependent mechanism by dendritic cells (DCs) that lead to CD4+ T cell activation [33][34][35][36][37]. Studies by Leclerc et al have validated this phenomenon, demonstrating a correlation between an increased Tn density on MUC6 and other peptides to enhance antigen internalization by APCs [38].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Immune Response Against the Thomsen-Friedenreich Tumor Antigen Using a Bivalent Entirely Carbohydrate Conjugate

et al. 2020

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The Thomsen-Friedenreich (TF) antigen is a key target for the development of anticancer vaccines, and this ongoing challenge remains relevant due to the poor immunogenicity of the TF antigen. To overcome this challenge, we adopted a bivalent conjugate design which introduced both the TF antigen and the Thomsen-nouveau (Tn) antigen onto the immunologically relevant polysaccharide A1 (PS A1). The immunological results in C57BL/6 mice revealed that the bivalent, Tn-TF-PS A1 conjugate increased the immune response towards the TF antigen as compared to the monovalent TF-PS A1. This phenomenon was first observed with enzyme-linked immunosorbent assay (ELISA) where the bivalent conjugate generated high titers of IgG antibodies where the monovalent conjugate generated an exclusive IgM response. Fluorescence-activated cell sorting (FACS) analysis also revealed increased binding events to the tumor cell lines MCF-7 and OVCAR-5, which are consistent with the enhanced tumor cell lysis observed in a complement dependent cytotoxicity (CDC) assay. The cytokine profile generated by the bivalent construct revealed increased pro-inflammatory cytokines IL-17 and IFN-γ. This increase in cytokine concentration was matched with an increase in cytokine producing cells as observed by ELISpot. We hypothesized the mechanisms for this phenomenon to involve the macrophage galactose N-acetylgalactosamine specific lectin 2 (MGL2). This hypothesis was supported by using biotinylated probes and recombinant MGL2 to measure carbohydrate-protein interactions.

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The Macrophage Galactose-Type C-Type Lectin (MGL) Modulates Regulatory T Cell Functions

Cited by 19 publications

References 26 publications

MGL Receptor and Immunity: When the Ligand Can Make the Difference

MGL Receptor and Immunity: When the Ligand Can Make the Difference

Human Macrophage Galactose‐Type Lectin (MGL) Recognizes the Outer Core of Escherichia coli Lipooligosaccharide

Enhanced Immune Response Against the Thomsen-Friedenreich Tumor Antigen Using a Bivalent Entirely Carbohydrate Conjugate

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