The Macrophage C-type Lectin Specific for Galactose/N-Acetylgalactosamine Is an Endocytic Receptor Expressed on Monocyte-derived Immature Dendritic Cells

Abstract

Lectins on antigen presenting cells are potentially involved in the antigen uptake and the cellular recognition and trafficking. Serial analysis of gene expression in monocyte-derived dendritic cells (DCs), monocytes, and macrophages revealed that 7 of the 19 C-type lectin mRNA were present in immature DCs. Two of these, the macrophage mannose receptor and the macrophage lectin specific for galactose/N-acetylgalactosamine (MGL), were found only in immature DCs, as confirmed by reverse transcriptase-PCR and flow cytometric analysis. By subcloning and sequencing the amplified mRNA, we obtained nucleotide sequences encoding seven different human MGL (hMGL) subtypes, which were apparently derived from alternatively spliced mRNA. In addition, the hMGL gene locus on human chromosome 17p13 contains one gene. A single nucleotide polymorphism was identified at a position in exon 3 that corresponds to the cytoplasmic region proximal to the transmembrane domain. Of all the splicing variants, the hMGL variant 6C was expressed at the highest levels on immature DCs from all donors tested. Immature DCs could incorporate ␣-GalNAc-modified soluble acrylamide polymers, and this was significantly inhibited by pretreatment of the cells with an anti-hMGL monoclonal antibody that blocks the lectin-carbohydrate interaction. We propose that hMGL is a marker of imDCs and that it functions as an endocytic receptor for glycosylated antigens. Dendritic cells (DCs)1 play a pivotal role in the immune system by processing and presenting a variety of antigens to T cells (1). The uptake of exogenous antigens is the first step in this process and is therefore a critical event that influences DC function. The uptake of glycoconjugates by DCs is potentially mediated by lectins, which are carbohydrate-binding proteins. There are at least four distinct lectin families in animal cells known as the C-type, S-type, P-type, and I-type lectins (2). Some lectins are known to participate in molecular and cellular trafficking in a manner that is dependent on the lectin type, its molecular architecture, and its subcellular localization. DCs are known to express a variety of lectins, particularly C-type lectins, but as yet their biological roles in DC function are unclear.How glycosylated antigen presentation is regulated and how this affects the subsequent immune responses has not yet been clarified. This is an important issue to investigate as it may improve our understanding of, for example, anti-tumor immunity to MUC1. MUC1 is a glycosylated membrane protein that frequently expresses truncated O-glycans such as the T (Gal␤1-3GalNAc-Thr/Ser) and Tn (GalNAc-Thr/Ser) antigens. MUC1 is an important candidate vaccine antigen as it is an antigen that is often overexpressed in solid tumors, including carcinoma of the breast, lung, pancreas, colon, and ovaries. MUC1-specific cytotoxic T lymphocytes have been isolated from draining lymph nodes of pancreatic and breast cancer patients, ascitic fluids of ovarian cancer patients, and peripheral blood mononuclear cell...

Lack of antigen-specific tissue remodeling in mice deficient in the macrophage galactose-type calcium-type lectin 1/CD301a

“…22 In humans, MGL-positive macrophages and DCs can be developed from monocytes. 47,48 It is likely that dermal MGL-positive cells are derived from these cells. Migration of dermal MGL1/2-positive cells from dermis to draining lymph nodes was shown to be initiated by IL-1.…”

Monocyte Adhesion to Xenogeneic Endothelium during Laminar Flow Is Dependent on α-Gal-Mediated Monocyte Activation

“…In addition to classical adhesion molecules, monocytes express lectins that bind to specific carbohydrate sequences on bacteria and glycosylated Ags (41,42). Preformed xenoreactive Abs target the major xenoantigen, ␣-gal, because of a common terminal carbohydrate sequence with bacterial ␣-gal, and similar cross-reactivity may occur between monocyte lectins and endothelial ␣-gal (39).…”

A C-Type Lectin MGL1/CD301a Plays an Anti-Inflammatory Role in Murine Experimental Colitis

“…15,16 In our previous reports, we found that MGL1 and/or MGL2 were mainly expressed on macrophages and immature DCs, and that these cells were observed mainly in the connective tissue of various organs, especially in skin, large intestines, and lymph nodes. 17 These lectins were found to be involved in the uptake of mucin-like GalNAc-conjugated polymers by murine bone marrow-derived and human monocytederived DCs, 18,19 which was thought to be an important process of antigen processing. Mgl1-deficient mice did not show obvious defects in lymphoid and erythroid homeostasis.…”