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The Ligands of C-Type Lectins

  • Amy J. Foster
  • Jessie H. Bird
  • Mattie S. M. Timmer
  • Bridget L. StockerEmail author
Chapter

Abstract

In this chapter, a comprehensive overview of the known ligands for the C-type lectins (CTLs) is provided. Emphasis has been placed on the chemical structure of the glycans that bind to the different CTLs and the amount of structural variation (or overlap) that each CTL can tolerate. In this way, both the synthetic carbohydrate chemist and the immunologist can more readily gain insight into the existing structure-activity space for the CTL ligands and, ideally, see areas of synergy that will help identify and refine the ligands for these receptors.

Keywords

C-type lectin Receptor Ligand Pathogen Immunity Carbohydrates Glycolipids 

13.1 Introduction

There has been much interest in identifying the ligands that bind to and activate C-type lectins (CTLs) and in determining how this ligand-receptor binding modulates the immune response. As illustrated in Table 13.1, most CTL ligands (CTLLs) are from exogenous sources, although several examples of endogenous CTLLs can also be found. Most CTLLs contain a glycan motif; however, the breath of CTLLs is diverse and also includes proteins and oligonucleotides, as well as molecules whose structure is still to be determined. There are also several CTLs, such as CLEC12B, CLEC1-1, DCAL-1, DCAR and mDCAR1, for which there are no known ligands. As previous chapters in this book have focussed on the biochemical pathways and immunomodulatory activities of the CTLs, our focus herein has been to showcase the CTLLs and, where relevant, to highlight the degree of structural variation each CTL can tolerate. By doing so, we hope to equip the reader with a more readily digestible data set on the vast array of CTLLs and to encourage natural products or synthetic chemists to identify new, or further refine, ligands for these receptors.
Table 13.1

C-type lectins and their ligands

Lectin

Structure

Origin

Lectin

Structure

Origin

Dectin-2

Man7-9GlcNAc2

Glycan array

SIGN-R1

Man, Fuc, Lex, Ley, SLex

Glycan array

O-linked mannobiose-rich glycoproteins

Malassezia

Lacto-N-fucopentaose III (LNFP III)

Milk

Mannose-capped LAM

Mycobacterium

Dextran

Leuconostoc spp.

MDL-1

Unidentified

Endogenous

LSECtin

GlcNAc, Fuc

Glycan array

BDCA-2

Non-sialylated complex-type glycans

Glycan array

Langerin

Man, Fuc, GlcNAc, Man9GlcNAc2

Glycan array

Asialo-galactosyl-oligosaccharides

Chemical synthesis

Ley, 6′-SO4-Lex

Glycan array

Mincle

Trehalose dimycolate (TDM)

Mycobacterium

 

Dextran sulphate

Leuconostoc spp.

Trehalose diesters (TDE) and trehalose monoesters (TME)

Chemical synthesis

 

6-SO4-Gal, 6-SO4-GlcNAc, 6′-SO4-LacNAc

Polyacrylamide (PAA)-conjugates

α-Mannose and mannitol derivatives

Malassezia

 

Heparan sulphate (HS) and chondroitin sulphate (CS)

Porcine

MCL

TDM

Mycobacterium

 

Heparin (HEP)

Chemical synthesis

Dectin-1

T-cell ligand

Endogenous

 

Laminarin (β-1,6- and β-1,3-glucan)

Laminaria digitata (brown alga)

Unidentified N-glycans

Tumour cells

 

Fucoidan (α-1,3/4-(2/3-SO4)-fucan)

Fucus vesiculosus

Linear and branched β-1,3-glucans

Plant and fungal cell walls

 

Galactan (β-1,4-)

Plant

CLEC-2

Rhodocytin

Snake venom

 

Mannan (β-1,4-)

Saccharomyces cerevisiae

NeuAcα2-3Galα1-3(NeuAcα2-6) GalNAcα

Endogenous podoplanin

 

Dextran (α-1,3-branched α-1,6-glucans)

Leuconostoc spp.

Fucoidan (α-1,3/4-(2/3-SO4)-fucan)

Fucus vesiculosus

 

Zymosan (β-1,3-glucan)

Saccharomyces cerevisiae

DNGR-1

Filamentous actin (F-actin)

Necrotic cells

 

Mannose and β-glucans

Fungi

SIGN-R3

Dextran (α-1,3-branched α-1,6-glucans)

Leuconostoc spp.

MGL

α- and β-GalNAc (Tn antigen), LacdiNAc, Sialyl-Tn

Endogenous

Zymosan (β-1,3-glucan)

Saccharomyces cerevisiae

MUC-1 and Muc-2

Endogenous

High mannose

Glycan array

MGL-1

Gal, GalNAc, Lex, Lea

Glycan array

Fucosylated glycans (Lea and Leb)

Glycan array

Gb5

Chemical synthesis

ManLAM and LM

Mycobacterium

MGL-2

α- and β-GalNAc, Gal, Tn, TF, core 2,

Glycan array

Unidentified

Leishmania, commensal fungi and bacteria

GalNAc

Endogenous

DCIR

HIV-1 glycoprotein 140 (gp140)

HIV

LOX-1

Modified lipoprotein

Chemically modified endogenous

Sulfo-Lea, Lea, Leb

Synthetic PAA conjugates

Advanced glycation end product (AGE)

Synthetic BSA Conjugates

Manα1-3(Manα1-6)Man

Synthetic BSA conjugates

Polyinosinic acid (Poly I)

Synthetic

Gal, GalNAc, Glc and GlcNAc

Synthetic BSA conjugates

Carrageenan (type III Kappa)

Red algae

DCIR-2

N-glycan with bisecting GlcNAc

Chemical synthesis

 

Phosphatidylserine, phosphatidylinositol

Liposomes

MICL

Mono sodium urate (MSU) crystals

Synthetic

 

Phosphatidic acid, cardiolipin, phosphatidylglycerol

Liposomes

LY49Q

MHC-I

Endogenous

MR

ManLAM

Mycobacterium

DC-SIGN

Lex, Ley, LDNF

Schistosoma mansoni

 

Mannan

Saccharomyces cerevisiae

ManLAM, PIM, α-glucan

Mycobacterium

 

Fuc, Man

Neoglycoproteins

Man9GlcNAc2

Glycan array

 

3- and 4-SO4-GalNAc

Chemical synthesis

Mannan

Saccharomyces cerevisiae

 

Chondroitin sulphates A and B

Bovine and porcine

TAG-72, semen clusterin

Endogenous

 

SO4-Lex, SO4-Lea

Chemical synthesis

HIV-1 glycoprotein 120 (gp120)

HIV

 

High-mannose-containing glycoproteins

Endogenous

L-SIGN

Man9GlcNAc2

Chemical synthesis

DEC-205

CpG oligonucleotides

Chemical synthesis

13.2 C-Type Lectins Containing ITAM-Like Signalling Motifs

13.2.1 Dectin-2

Dectin-2, otherwise known as CLEC6A, is an FcRγ-coupled receptor found on macrophages (Mφs), monocytes and several subsets of dendritic cells (DCs) (Sancho and Reis e Sousa 2012). Binding assays have demonstrated that the extracellular portion of Dectin-2 can recognise the hyphal portions of Candida albicans, Microsporum audouinii and Trichophyton rubrum (Sato et al. 2006). In addition to fungal species, Dectin-2 has been shown to recognise Schistosoma mansoni egg antigens (Ritter et al. 2010). Although the exact ligand structure for Dectin-2 is not well defined, carbohydrate binding studies have revealed that Dectin-2 recognises high-mannose structures such as Man9GlcNAc2 (Fig. 13.1) (McGreal et al. 2006). Here, Dectin-2 was screened against 109 synthetic carbohydrates, and although Dectin-2 displayed the highest specificity for Man9GlcNAc2, it also recognised Man8GlcNAc2 and Man7GlcNAc2. Dectin-2 has also been shown to bind α-mannans of fungal cell walls (Saijo et al. 2010).
Fig. 13.1

Representative ligands for ITAM-like and Hem-ITAM-like receptors

Dectin-2, in cooperation with Mincle, has been shown to recognise the pathogenic fungus Malassezia. Using solvent-based fractionation, it was determined that Dectin-2 recognised the hydrophilic components of Malassezia, and with the aid of mass spectrometry and NMR analysis, an O-linked mannobiose-rich glycoprotein was determined to be the Dectin-2 ligand (Ishikawa et al. 2013). The mannose-capped lipoarabinomannan LAM from mycobacterial species has also been identified as a ligand for Dectin-2 (Yonekawa et al. 2014). Moreover, Dectin-2 recognises a ligand on CD4+CD25+ T cells; however, the exact ligand structure is unknown (Aragane et al. 2003).

13.2.2 MDL-1

MDL-1 (myeloid DAP12-associating lectin-1 or CLEC5A) is a CTL expressed on the cell surface of monocytes, Mφs and osteoclasts (Sancho and Reis e Sousa 2012). MDL-1 has been shown to bind the dengue virion (DV), resulting in DAP12 phosphorylation and cytokine production (Chen et al. 2008). If, on the other hand, the DV-MDL-1 interaction is blocked with monoclonal antibodies, symptoms associated with DV infection, such as plasma leakage and vital organ haemorrhaging, were reduced in a murine model. In addition to the dengue virion, MDL-1 also directly interacts with the Japanese encephalitis virus and induces cytokine production by Mφs (Chen et al. 2012). MDL-1 knockout or blocking with an MDL-1 antibody was shown to reduce the symptoms of arthritis, which indicates that there may be an unidentified self-ligand for MDL-1 (Joyce-Shaikh et al. 2010). The same authors later proposed that galectin-9 was a ligand for MDL-1 and demonstrated that treatment with galectin-9 intensified disease in a murine model of arthritis (Joyce-Shaikh et al. 2014).

13.2.3 BDCA-2

Blood dendritic cell antigen 2 (BDCA-2, also known as CLEC4C or CD303) belongs to the group II ITAM-coupled family of myeloid CLRs. BDCA-2 expression is restricted to human plasmacytoid DCs (Dzionek et al. 2001), and the targeting of antigens to this receptor has been suggested to be a promising strategy for inducing antigen-specific tolerance. BDCA-2 was first shown to bind the HIV protein, gp120, leading to the inhibition of toll-like receptor (TLR)-9-mediated activation and interferon (IFN)-γ secretion in plasmacytoid DCs (Martinelli et al. 2007), while more recently it was determined that BDCA-2 recognises complex-type sugars that have lost their terminal sialic residues (Fig. 13.1), such as Galβ1-4GlcNAcβ1-2Manα1-3(Galβ1-4GlcNAcβ1-2Manα1-6)-Manβ1-4GlcNAcβ1-4GlcNAcβ and Galβ1-3GlcNAcβ1-2Manα1-3(Galβ1-3GlcNAcβ1-2Manα1-6)-Manβ1-4GlcNAcβ1-4GlcNAcβ (Riboldi et al. 2011). The recognition of complex galactose-terminated glycans by BDCA-2 has been suggested to be a mechanism that tumour cells or invading pathogens use to downregulate IFN-γ production and immune surveillance.

13.2.4 Mincle

Macrophage-inducible C-type lectin (Mincle, CLEC4e or CLECf9) is a group II FcRγ-coupled receptor that is expressed in low levels on Mφs and DCs (Sancho and e Sousa 2012). In a ligand-binding study that employed an NFAT-GFP reporter cell line and Mincle-deficient mice, it was demonstrated that trehalose dimycolate (TDM), the most abundant glycolipid in the mycobacterial cell wall, is a ligand for Mincle (Ishikawa et al. 2009). TDMs consist of a trehalose disaccharide core bound to two mycolic acid chains, which can be of varying structural complexity (Fig. 13.1). Additionally, both human and murine Mincle have been shown to recognise the yeast species Candida albicans (Bugarcic et al. 2008; Wells et al. 2008) and the fungal species Malassezia (Yamasaki et al. 2009). In Malassezia fungal species, specific mannitol-containing ligands were identified as direct ligands for Mincle (Ishikawa et al. 2013). Mincle has also been shown to sense dead cells through a protein component of small nuclear ribonucleoprotein (SAP30) (Yamasaki et al. 2008).

Structure-activity relationship studies have since confirmed that many simple TDM synthetic analogues also bind Mincle. Specifically, long-chain trehalose diesters (TDEs), including trehalose dibehenate (TDB), have been found to lead to the robust activation of Mφs (Schoenen et al. 2010; Khan et al. 2011), while more recently it has been demonstrated that trehalose esters with only one lipid chain (trehalose monoesters, TMEs) can also bind and activate Mincle (Stocker et al. 2014). Moreover, functionalised trehalose glycolipids, including those containing fluorescent reporter groups or photoaffinity probes, have also been shown to bind and activate Mincle (Khan et al. 2013; Kodar et al. 2015). In addition to trehalose diesters, another mycobacterial immunostimulatory lipid, glycerol monomycolate, has been shown to activate human but not mouse Mincle (Hattori et al. 2014). Corynomycolic esters of trehalose (TDCM) were also found to be potent activators of both mouse and human Mincle, while 2-S-corynomycolic esters of glycerol were found to activate human but not mouse Mincle (van der Peet et al. 2015).

13.2.5 MCL

Macrophage C-type lectin (MCL or CLEC4d) is another FcRγ-coupled receptor that is constitutively expressed on myeloid cells (Sancho and Reis e Sousa 2012). MCL is thought to arise via a gene duplication of Mincle, and while MCL contains a calcium coordination site, it does not retain the exact EPN motif of Mincle (Sancho and Reis e Sousa 2012). The exact ligand structure of MCL is not well defined; however, MCL has been shown to bind TDM (Miyake et al. 2013; Furukawa et al. 2013).

13.3 C-Type Lectins Containing Hem-ITAM-Like Signalling Motifs

13.3.1 Dectin-1

Dectin-1 (also known as CLEC7a) was the first non-toll-like receptor shown to mediate its own intracellular signalling (Sancho and Reis e Sousa 2012). The receptor was originally found to recognise an endogenous T-cell ligand of unknown structure (Ariizumi et al. 2000) and has since been shown to bind other endogenous ligands including undefined N-glycans on the surface of tumour cells, which leads to tumour destruction by natural killer (NK) cells (Chiba et al. 2014), and vimentin (a type III intermediate filament protein) (Thiagarajan et al. 2013). An unknown ligand in mycobacteria also binds Dectin-1 (Yadav and Schorey 2006; Rothfuchs et al. 2007).

The most insight into the structure of the Dectin-1 ligands, however, concerns the ability of the receptor to bind glucans, particularly β-1,3-glucans (Fig. 13.1), which are found in the cell wall of plants and fungi (Brown and Gordon 2001; Sancho and Reis e Sousa 2012). Microarray studies suggest that ten to eleven β-1,3-linked glucose oligomers are required for optimal Dectin-1 binding, and while β-1,6-glucans of comparable length do not bind (Palma et al. 2006), branched β-1,3-glucans do bind to the receptor (Palma et al. 2006; Adams et al. 2008). More recent studies have demonstrated that smaller glucan mimetics can also bind Dectin-1, as evidenced by studies using synthetic β-glu6 containing an α-(1→3)-linked bond (Li et al. 2013) and di- and trimeric hydroxylamine-based mimetics (Ferry et al. 2014). In the latter study, the binding of the small oligosaccharide fragments was attributed to the increased hydrophobic interaction between the α-face of the di- or trisaccharide and the aromatic side chains of Trp 221 ad His 223 in the binding site of Dectin-1. A distinction has also been made between the binding of soluble and particulate glucans. Different downstream Dectin-1 signalling occurs when myeloid cells come into contract with particulate β-glucan, and in particular, that prolonged Dectin-1 signalling occurs when myeloid cells come into contact with large β-glucan particles (Sancho and Reis e Sousa 2012). A few polysaccharides can also interfere with the binding of β-glucans to Dectin-1, thereby thwarting the host immune response. These include chitin-like components found on sclerotic cells in murine models of chromoblastomycosis (Dong et al. 2014) and α-(1,3)-glucan, which is a cell wall constituent of most fungal respiratory pathogens (Rappleye et al. 2007).

13.3.2 CLEC-2

Like Dectin-1, CLEC-2 (also known as CLEC-1B or CLEC-2B) also belongs to Group V of the non-calcium-dependent CTLs. CLEC-2 was discovered with CLEC-1 in a bioinformatics screen for NK receptors, and while mRNA for CLEC-2 has been found in bone marrow cells, DCs, monocytes, granulocytes and some NK cell populations, most studies have focussed on the role of CLEC-2 on platelets (Plato et al. 2013). Several CLEC-2 ligands have been identified, including rhodocytin (aggretin), which is an exogenous multimeric protein found in snake venom that leads to platelet activation and aggregation and subsequent coagulation of the blood (Suzuki-Inoue et al. 2011). Soon thereafter, the endogenous protein podoplanin was found to be a ligand for CLEC-2 (Suzuki-Inoue et al. 2007). Podoplanin is found in multiple cell types such as lymphatic endothelial cells, type I lung alveolar cells and in some cancer cells and consists of the sialylated glycan NeuAcα2-3Galβ1-3(NeuAcα2-6)GalNAc (Fig. 13.1) conjugated via an α-linkage to Thr52 in the platelet aggregation-stimulating domain (Kaneko et al. 2007). Both the disialyl core and the stereostructure of the protein were found to be critical for CLEC-2 binding, as evidenced by the observation that CLEC-2-Fc terminal deletion mutants and human podoplanin glycopeptides containing truncated glycans were unable to bind the receptor (Kato et al. 2008). Fucoidan (Fig. 13.1), which is a sulphated polysaccharide from Fucus vesiculosus, is an agonist for CLEC-2 (Manne et al. 2013), and HIV is also thought to be recognised by CLEC-2, although it is proposed that this recognition is due to the incorporation of a host protein into HIV during budding (Suzuki-Inoue et al. 2011). Finally, a series of synthetically prepared nucleic acid CLEC-2 ligands (aptamers) were identified using the systematic evolution of ligands by exponential enrichment (SELEX) methodology (Layzer et al. 2010).

13.3.3 DNGR-1

The DC, NK lectin group receptor-1 (DNGR-1), also known as CLEC9A, is expressed on specific subsets of DCs (Sancho and Reis e Sousa 2012). The receptor recognises filamentous actin (F-actin), which is exposed on the surface of necrotic cells and thus serves as an evolutionarily conserved damage-associated molecular pattern (Ahrens et al. 2012; Zhang et al. 2012). The binding of F-actin to DNGR-1 does not lead to pro-inflammatory responses, but, rather, signalling from the receptor is required for antigen cross-presentation and effective immunity (Plato et al. 2013). The ability of DNGR-1 to promote antigen cross-presentation has seen interest in the development of a peptide-conjugate vaccine via use of an anti-DNGR-1 antibody conjugated to the tumour-associated glycoprotein antigen, MUC1 (Picco et al. 2014).

13.3.4 SIGN-R3

Mouse SIGN-R3 (CD209d) is a receptor with endocytic activity and is part of a cluster of mouse SIGN-R genes that are highly homologous to human DC-SIGN; although unlike human DC-SIGN, mouse SIGN-R3 signals via a Syk-dependent pathway (Sancho and Reis e Sousa 2012). Ligand studies using transfected non-macrophage cell lines demonstrated that SIGN-R3 endocytosed dextran of 40 kDa or greater and zymosan (Takahara et al. 2004). A comprehensive glycan array analysis further refined the SIGN-R3 ligands and demonstrated that SIGN-R3 preferentially binds to high-mannose glycans and fucosylated glycans, particularly Lewisa (Lea) and Leb antigens (Fig. 13.1) (Galustian et al. 2004), with subsequent array studies supporting these findings (Powlesland et al. 2006). SIGN-R3 has been found to contribute to early host resistance to M. tuberculosis infection with mycobaterial ManLAM and LM, but not AraLAM, binding and activating the receptor (Tanne et al. 2009). More recently, SIGN-R3 has been shown to play a role in leishmaniasis infection (Lefèvre et al. 2013) and to recognise ligands in commensal fungi and bacteria thereby potentially mediating colitis (Eriksson et al. 2013; Lightfoot et al. 2015); however, in each study, the specific ligand was not identified.

13.4 C-Type Lectins Containing ITIM-Like Signalling Motifs

13.4.1 DCIR

The C-type lectin dendritic cell immunoreceptor (DCIR) is an ITIM-coupled receptor. Human DCIR (CLEC4a) is expressed in monocytes, Mφs, granulocytes, B cells and DCs (Sancho and Reis e Sousa 2012). It has been demonstrated that DCIR can bind HIV-1 (Lambert et al. 2008), and while the specific ligand was not identified during this study, later work demonstrated that DCIR interacts with Leb and Lea (Fig. 13.2), mannotriose and sulfo-Lea (Fig. 13.2) as well as the HIV-1-type glycoprotein, gp140 (Bloem et al. 2014). In a competitive binding study that compared the binding characteristics of several CTLs, DCIR was found to bind mannose- and fucose-based ligands as well as thio-linked Gal-, GalNAc-, Glc- and GlcNAc-BSA (Lee et al. 2011). In an additional study, it was demonstrated that purified DCIR could bind the glycan structures Leb and Man3; however, this binding was not detected when the DCIR was expressed on the cell surface (Bloem et al. 2013).
Fig. 13.2

Representative ligands for ITIM-like and ITAM-ITIM-independent CTLs

13.4.2 DCIR-1 and DCIR-2

Four DCIR homologues have been identified in mice (DCIR-1-4); however, only DCIR-1 and DCIR-2 contain an ITIM sequence. DCIR-1 is expressed in B cells, monocytes, Mφs and DCs; however, very little is known about its ligands (Sancho and Reis e Sousa 2012). DCIR-2, on the other hand, is expressed on DCs and has been found to specifically bind N-glycans that incorporate bisecting N-acetyl-glucosamine (a β-GlcNAc moiety attached to the N-glycan β-mannose 4-position) (Nagae et al. 2013). Here, the authors noted that DCIR-2 primarily recognises two residues including the GlcNAcβ1-2Manα1-3- and bisecting GlcNAc residues (Fig. 13.2).

13.4.3 MICL

Human myeloid inhibitory C-type lectin (MICL also known as DCAL-2, KLRL-1, CLL-1 and CLEC-12a) is an ITIM-coupled receptor expressed in granulocytes, monocytes, Mφs and DCs (Sancho and Reis e Sousa 2012). Murine MICL on the other hand is expressed in myeloid cells, B cells, CD8+ T cells and bone marrow NK cells. Using flow cytometry and an Fc-mMICL fusion protein, MICL was found to bind several endogenous ligands from the heart, lung, liver, spleen and kidney (Pyz et al. 2008). More recently, MICL was determined to be a receptor for dead cells derived from 293T cells or thymocytes (Neumann et al. 2014). Here, ligand-binding studies demonstrated that both human and mouse MICL can recognise uric acid crystals (monosodium urate, Fig. 13.2), which are well-known cell death danger signals (Neumann et al. 2014).

13.4.4 LY49Q

Mouse Ly49Q (Klral7) is an inhibitory receptor that is expressed in Ly6C/G+ myeloid precursors, immature monocytes and plasmacytoid DCs (Sancho and Reis e Sousa 2012). Reporter cell analysis was employed to demonstrate that H-2b-derived tumour cells contain a high-affinity MHC-Ia-like ligand for LY49Q (Tai et al. 2007). In a subsequent study, LY49Q was identified as a direct receptor for MHC-I in mice (Scarpellino et al. 2007).

13.5 ITAM-ITIM-Independent C-Type Lectins

13.5.1 DC-SIGN

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), also known as CD209, is a CTL involved in DC-T-cell contact. DC-SIGN has a single carbohydrate recognition domain (CRD) and binds branched D-mannose and L-fucose motifs common on pathogen surfaces (Sancho and Reis e Sousa 2012), with clustering of the lectins resulting in the formation of tetramers to enhance ligand binding (Mitchell et al. 2001). High-mannose oligosaccharide ligands include mannan, mannosylated lipoarabinomannan (ManLAM, Fig. 13.2) (Maeda et al. 2003), phosphatidyl-myo-inositol mannosides (PIM, Fig. 13.2) (Driessen et al. 2009) and Man9GlcNAc2 (Fig. 13.1), whereby the latter binds DC-SIGN with 130 times higher affinity than mannose (Mitchell et al. 2001). DC-SIGN has a higher affinity for L-fucose than mannose and recognises branched fucosylated structures with terminal galactose residues, such as the Lewis antigens (Coombs et al. 2005), in particular Lex and possibly LDNF (Fig. 13.2) (van Die et al. 2003). DC-SIGN binds Helicobacter pylori (Miszczyk et al. 2012) and S. mansoni (Meyer et al. 2005) through the Lex and Ley antigens, while Mycobacterium tuberculosis is recognised via ManLAM (Maeda et al. 2003), PIM (Driessen et al. 2009) and α-glucan (Geurtsen et al. 2009), as well as further unidentified ligands (Ehlers 2010). Although this implies broad specificity for branched sugars, DC-SIGN discriminates between ligands through secondary binding sites and the α/β-linkage of adjacent saccharides (van Die et al. 2003). The signalling pathways induced by DC-SIGN are dependent on the nature of the ligand, leading to endocytosis or modulation of gene expression (Sancho and Reis e Sousa 2012). Endogenous ligands include tumour-associated glycoprotein-72 (TAG-72) (Laskarin et al. 2011) and semen clusterin (Sabatte et al. 2011), while DC-SIGN acts as a receptor for HIV through binding to the HIV-1 gp120 envelope protein (Curtis et al. 1992).

13.5.2 L-SIGN

L-SIGN or DC-SIGNR (also known as CD299, CD209L and CLEC4M) is a type II transmembrane C-type lectin receptor with 77 % sequence homology to DC-SIGN. In contrast to DC-SIGN which is expressed on DCs, L-SIGN is highly expressed on liver sinusoidal cells, endothelial vascular cells and in the lymph nodes. Like DC-SIGN, L-SIGN has high-affinity binding to a variety of ligands, including ICAM-3, HIV gp120-binding protein, simian immunodeficiency virus, Ebola virus, hepatitis C virus and respiratory syncytial virus. The CRD of L-SIGN binds the Man9GlcNAc2 oligosaccharide (Fig. 13.1) 17-fold more tightly than mannose, and its affinity for a glycopeptide bearing two Man9GlcNAc2 oligosaccharides is further increased by fivefold to 25-fold. These results indicate that the CRDs contain extended or secondary oligosaccharide binding sites. When the CRDs are clustered in the tetrameric extracellular domain, their arrangement provides a means of amplifying specificity for multiple glycans on host molecules targeted by DC-SIGN and L-SIGN (Mitchell et al. 2001).

13.5.3 SIGN-R1

The mouse CTL-specific ICAM-3 grabbing nonintegrin-related 1 (SIGN-R1, CD209b) is a homologue of hDC-SIGN and is expressed on a limited subset of Mφs and endothelial cells with a cell-specific expression similar to that of hL-SIGN. SIGN-R1 binds mannose- and fucose-containing ligands and Lewis blood antigens, thereby mirroring the specificity of hDC-SIGN and hL-SIGN, but in addition, SIGN-R1 also interacts with sialylated Lex (Galustian et al. 2004; Koppel et al. 2005). Lacto-N-fucopentaose III (LNFPIII, Fig. 13.2) binds to the surface of cells transfected with SIGN-R1, and binding of LNFPIII-NGC to SIGN-R1 has been demonstrated by ELISA (Srivastava et al. 2014). SIGN-R1 binds zymosan, a glucan with repeating glucose units connected by β-1,3-glycosidic linkages, and the capsular polysaccharide of Streptococcus pneumoniae, and while SIGN-R1-Fc did not interact with dextran, which contains a combination of α-1,3- and α-1,6-glucose linkages, cellular-expressed SIGN-R1 does interact with dextran, as demonstrated by several groups (Geijtenbeek et al. 2002; Kang et al. 2003).

13.5.4 LSECtin

Liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin, CLEC4G) is a ∼40 kDa type II integral membrane protein with a single C-type lectin-like domain, closest in homology to DC-SIGNR, DC-SIGN and CD23 (Liu et al. 2004). LSECtin functions as an attachment factor for Ebola virus and SARS, but it does not bind HIV or hepatitis C virus (Gramberg et al. 2005). LSECtin exhibits ligand-induced internalisation, and its sugar recognition specificity differs from that of DC-SIGN, as sugar-binding studies indicate that LSECtin specifically recognises N-acetyl-glucosamine (Dominguez-Soto et al. 2007) and l-fucose (Liu et al. 2004), whereas no LSECtin binding to mannan, N-acetyl-galactosamine and galactose were observed. The presence of LSECtin on myeloid cells should therefore contribute to expanding their antigen-capture and pathogen-recognition capabilities.

13.5.5 Langerin

Langerin (CLEC4K, CD207) is a type II transmembrane receptor with an extracellular region consisting of a neck and a C-terminal C-type CRD and is highly expressed on Langerhans cells, CD103+ DCs and splenic CD8+ DCs. Langerin recognises a wide array of carbohydrates including mannose, fucose and GlcNAc structures and especially Man9GlcNAc2 (Stambach et al. 2003). Langerin also recognises the difucosylated oligosaccharide Ley (Holla et al. 2011) and Lex-type sequences that are sulphated at the 6-position of the outer galactose (6′-sulfo-3′-SLex, Fig. 13.3). This specificity is unique among the CTLs and contrasts markedly with the selectins which bind the analogous Lex structures that are sulphated at the 3-position of the galactose. Of the sulphated saccharides, Langerin has also been shown to bind dextran-sulphate (Galustian et al. 2004) and 6-sulphated GlcNAc and especially 6′-sulfo-LacNAc (Tateno et al. 2010), whereas no binding was observed for either its positional isomer, 6-sulfo-LacNAc, or its unsulphated form. Langerin also binds to glioblastoma tissues via Gal-6-sulphated glycans (Tateno et al. 2010). Taken together, this suggests that the sulphate at C-6 of the non-reducing end sugar might be important for Langerin recognition.
Fig. 13.3

Representative ligands for ITAM-ITIM-independent CTLs

Other studies have shown that glycosaminoglycans such as heparan sulphate (HS) and chondroitin sulphate (CS) (preferentially 4-O-sulphated) interact with Langerin through a Ca2+-independent glycosaminoglycan (GAG)-specific binding site (Chabrol et al. 2012). Depending on ligand size, there are two binding modes for HS/heparin (HEP) oligosaccharides: a Ca2+-dependent mode for small HEP trisaccharides and binding at a positively charged groove at the interface of two CRDs and the neck domain for large (6 kDa) HEP oligosaccharides (Muñoz-García et al. 2015). Further, polysaccharides found to bind Fc-Langerin include laminarin, fucoidan, galactan and α-mannan (Hsu et al. 2009), and langerin was shown to bind to high molecular weight dextran (250–2,000 kDa) and zymosan, although binding was inhibited by mannan (Takahara et al. 2004).

Langerin binds to a variety of microorganisms: langerin is a receptor for Yersinia pestis phagocytosis and promotes dissemination (Yang et al. 2015), and carbohydrate-dependent binding of langerin to a cell wall glycoprotein of Mycobacterium leprae has been observed (Kim et al. 2015). Langerin binds HIV-1, which prevents transmission (De Witte et al. 2007). Also Candida and Saccharomyces species and Malassezia furfur are recognised by langerin, but very weak binding was observed to Cryptococcus gattii and Cryptococcus neoformans. No binding was observed for the Gram-positive bacteria Staphylococcus aureus or Gram-negative Escherichia coli and Salmonella typhimurium (Takahara et al. 2004). Notably, Langerin has been identified as the primary fungal receptor on Langerhans cells (LCs), since the interaction of LCs with fungi was blocked by antibodies against Langerin. Langerin recognises both mannose and β-glucans present on fungal cell walls and appears to be an important fungal pathogen receptor on human LCs that recognises pathogenic and commensal fungi (De Jong et al. 2010). Interestingly, common polymorphisms in human langerin change the receptor specificity for glycan ligands (Feinberg et al. 2013).

13.5.6 MGL

Macrophage galactose-type lectin (MGL, CLEC-10A, CD301, DC-ASGPR), a type II transmembrane receptor, is expressed on immature and tolerogenic DCs, Mφs, dermal CD1a+ DCs and blood CD1c+ myeloid DCs. MGL specifically recognises α- and β-linked GalNAc residues (Suzuki et al. 1996), including the Tn antigen and LacdiNAc (Fig. 13.3) and 6-substituted GalNAc derivatives such as the sialyl-Tn antigen (Mortezai et al. 2013). In addition, MGL binds to CD45 on effector T cells and interacts with lymphatic endothelial cells through an unknown ligand. Of the self-antigens, MGL binds to the GalNAc moieties on the tumour-derived MUC1 and MUC2 glycoproteins (Iida et al. 1999). Pathogenic organisms that engage with MGL include Neisseria gonorrhoeae, Campylobacter jejuni, Ebola virus, Schistosoma mansoni (Van Vliet et al. 2005) and Trichuris suis (Van Kooyk et al. 2015).

13.5.7 MGL-1

The mouse CTL MGL-1 (CD301a, CLEC-10a) is one of the two hMGL orthologues with distinct carbohydrate recognition. Early studies demonstrated that mMGL-1 recognises galactose-related structures such as Lex (Tsuiji et al. 2002). Using a glycan array, murine MGL-1 was found to be highly specific for Lex and Lea structures. The generation of MGL-1-Fc proteins allowed the identification of high endothelial venules as ligands in the lymph nodes (Singh et al. 2009), while the incubation of arrays with an MGL-1-hFc fusion protein showed up to tenfold increased binding to multiantennary N-glycans displaying Lex structures compared to monovalent Lex trisaccharide (Eriksson et al. 2014). In another glycan array, MGL-1 was found to bind to a range of terminal galactose and GalNAc glycans, which is consistent with the known galactose-binding motif QPD in the CRD of MGL-1. In these studies, MGL-1-Fc was found to bind the stage-specific tumour antigen Gb5 (Fig. 13.3), which suggests an association of this interaction with tumour progression (Maglinao et al. 2014).

MGL-1 also binds Trypanosoma cruzi, presumably through surface-expressed galactose moieties (Vázquez et al. 2014), and triggers phosphorylation of Raf-1 in response to products excreted/secreted by the helminth parasite Taenia crassiceps, thereby being involved in the induction of Th2 responses against the parasite (Terrazas et al. 2013). MGL-1 acts as an attachment and entry receptor for influenza virus, independent of sialic acid expression (Upham et al. 2010; Ng et al. 2014). Recombinant MGL-1 was found to bind both Streptococcus sp. and Lactobacillus sp. among commensal bacteria isolated from mesenteric lymph nodes of mice treated with dextran sulphate sodium salt (DSS) (Saba et al. 2009).

13.5.8 MGL-2

MGL-2 (CD301b) recognises carbohydrates containing GalNAc, which is similar to the carbohydrate specificity of human MGL (Tsuiji et al. 2002). Using a glycan array, MGL-2 was found to recognise GalNAc and galactose, including the O-linked Tn- and TF-antigens and core 2 O-GalNAc glycans (Fig. 13.3). Strikingly, MGL-2 interacted strongly with adenocarcinoma cells, suggesting a potential role in tumour immunity (Singh et al. 2009). MGL-2 specifically binds tumour-associated GalNAc, and modification of an antigen with GalNAc targeted the antigen specifically to the MGL-2 on bone marrow-derived (BM) DCs and splenic DCs and promoted antigen internalisation in DCs and presentation to CD4 T cells, as well as differentiation of IFN-γ producing CD4 T cells (Singh et al. 2011). Mice infected with the natural rodent hookworm pathogen Nippostrongylus brasiliensis required MGL-2+ DCs for efficient Th2 development, but these cells were dispensable for T follicular helper or B-cell responses, as MGL-2+ DC-depleted animals showed normal levels of IgG1 and IgE antibodies (Kumamoto et al. 2013).

13.5.9 LOX-1

Lectin-like oxidised low-density lipoprotein (ox-LDL) receptor-1 (LOX-1, CLEC8A) has been identified as the receptor for five diverse ligand classes (Chen and Du 2007). The first class is modified lipoproteins including ox-LDL (Sawamura et al. 1997), hypochlorite-modified high-density lipoprotein (HOCl-HDL) (Marsche et al. 2001), carbamylated LDL (Apostolov et al. 2009), electronegative LDL (Lu et al. 2009), apolipoprotein B (Gillotte et al. 2000; Okamura et al. 2013, and advanced glycation end product (AGE) proteins (Jono et al. 2002). Native LDL is not recognised by LOX-1 (Yoshimoto et al. 2011), while some studies suggest that acetylated LDL is recognised (Shi et al. 2001), and others indicate it is not (Moriwaki et al. 1998). The second group of ligands are polyanionic structures including polyinosinic acid and carrageenan (Moriwaki et al. 1998). Anionic phospholipids are also recognised, including the cellular ligands phosphatidylserine (PS) and phosphatidylinositol (PI) (Fig. 13.3) (Oka et al. 1998), which are expressed on apoptotic and aged cells. Cellular ligands comprise the fourth group; however, the exact molecules recognised by LOX-1 on these cells are less well defined. Apoptotic cells (Oka et al. 1998), platelets (Kakutani et al. 2000) and both Gram-negative bacteria such as Escherichia coli and Gram-positive bacteria such as Staphylococcus aureus are recognised (Shimaoka et al. 2001). Finally, other macromolecules that act as LOX-1 ligands include bile salt-dependent lipase (Chen and Du 2007), heats-hock proteins (Murshid et al. 2011) and C-reactive proteins (Shih et al. 2009).

13.5.10 Mannose Receptor

The mannose receptor (MR), also known as CD-206, is a 175-kDa transmembrane C-type lectin widely expressed on tissue Mφs and DCs (Martinez-Pomares 2012). MR binds branched high-mannose-containing motifs, such as ManLAM (Kang et al. 2005) and mannan (Taylor et al. 1992), and while MR preferentially binds branched α-linked oligomannoses, its specificity is not limited to D-mannose-containing glycoconjugates. Affinity binding competition studies demonstrate that MR binds to glycoconjugates with the following specificity: l-Fuc = d-Man > d-GlcNac ≈ d-Glc > d-Xyl >> d-Gal = l-Ara = d-Fuc, while galactose and GalNAc do not bind (Shepherd et al. 1981). Ligand binding is mediated by eight tandem CRDs, and while CRDs 1–3 have weak ligand binding, CRD-4 is able to elicit monosaccharide binding, and CRDs 4–8 are necessary for the binding of complex glycans (Mullin et al. 1994; Taylor et al. 1992). MR has a secondary lectin binding site located at the cysteine-rich N-terminus of the protein, and this mediates binding to sulphated sugar residues (Leteux et al. 2000), with special affinity for GalNAc residues sulphated at the 3- and 4-positions, including chondroitin sulphates A and B and sulphated Lex and Lea.

Given the breath of glycans to which MR binds, the receptor is thus able to recognise a variety of pathogens including viruses, fungi, bacteria and helminths, resulting in their phagocytosis, and many specific allergens including Ara h 1 (peanut), Bla g2 (cockroach), Can f 1 (dog), Der p 1 (mite), Der p 2 (mite) and Fel d 1(cat) (Martinez-Pomares 2012). MR also acts as a molecular scavenger, and indeed the receptor was initially identified due to its ability to clear high-mannose-containing glycoproteins, such as lysosomal enzymes, from blood (Stahl et al. 1976; Martinez-Pomares 2012). Other endogenous ligands include salivary amylase, tissue plasminogen activator, thyroglobulin and serum secretory phospholipase A2-IIA (Martinez-Pomares 2012).

13.5.11 DEC-205

Mouse DEC-205 (CD205), a CTL that is highly expressed on CD8α+ DCs and to a lesser degree on macrophages, T cells, B cells, and granulocytes, recognises plasminogen activator (PLA) expressing bacteria such as Yersinia pestis and Escherichia coli but not the PLA-negative controls (Sancho and Reis e Sousa 2012; Zhang et al. 2008). Both murine and human DEC-205 (which is widely expressed) act as receptors for dying cells (Shrimpton et al. 2009).

13.6 Summary

As evidenced above, the repertoire of CTLs and their associated ligands is immense. Some CTLs have been studied for many years, and, accordingly, their associated ligands are, by and large, well defined; however, for other CTLs, and especially those that appear to accommodate a vast array of ligands, much remains unknown about the specificity of ligand binding and how this influences the immune response. It is without a doubt that insight into the specific ligand structure for such CTLs will further assist in understanding how pathogens can either be recognised by the immune system or how they can thwart the immune response. Moreover, the association between CTLs and endogenous ligands can assist in understanding deleterious cellular process such as tumour growth and also regular cellular ‘housekeeping’ processes, such as debris clearance. Thus, it is imperative that immunologists and chemists continue to work closely together in order to determine how CTL-ligand interactions influence the many varied aspects of the immunology.

References

  1. Adams EL, Rice PJ, Graves B et al (2008) Differential high-affinity interaction of Dectin-1 with natural or synthetic glucans is dependent upon primary structure and is influenced by polymer chain length and side-chain branching. J Pharmacol Exp Ther 325:115–123PubMedCrossRefGoogle Scholar
  2. Ahrens S, Zelenay S, Sancho D et al (2012) F-Actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36:635–645PubMedCrossRefGoogle Scholar
  3. Apostolov EO, Shah SV, Ray D et al (2009) Scavenger receptors of endothelial cells mediate the uptake and cellular proatherogenic effects of carbamylated LDL. Arterioscler Thromb Vasc Biol 29:1622–1630PubMedCrossRefGoogle Scholar
  4. Aragane Y, Maeda A, Schwarz A et al (2003) Involvement of Dectin-2 in ultraviolet radiation-induced tolerance. J Immunol 171:3801–3807PubMedCrossRefGoogle Scholar
  5. Ariizumi K, Shen GL, Shikano S et al (2000) Identification of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloning. J Biol Chem 275:20157–20167PubMedCrossRefGoogle Scholar
  6. Bloem K, Vuist IM, van der Plas AJ et al (2013) Ligand binding and signaling of dendritic cell immunoreceptor (DCIR) is modulated by the glycosylation of the carbohydrate recognition domain. PLoS ONE 8, e66266PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bloem K, Vuist IM, van den Berk M et al (2014) DCIR interacts with ligands from both endogenous and pathogenic origin. Immunol Lett 158:33–41PubMedCrossRefGoogle Scholar
  8. Brown GD, Gordon S (2001) Immune recognition: a new receptor for beta-glucans. Nature 413:36–37PubMedCrossRefGoogle Scholar
  9. Burgarcic A, Hitchens K, Beckhouse AG et al (2008) Human and mouse macrophage-inducible C-type lectin (Mincle) bind Candida albicans. Glycobiology 18:679–685CrossRefGoogle Scholar
  10. Chabrol E, Nurisso A, Daina A et al (2012) Glycosaminoglycans are interactants of Langerin: comparison with gp120 highlights an unexpected calcium-independent binding mode. PLoS ONE 7, e50722PubMedPubMedCentralCrossRefGoogle Scholar
  11. Chen XP, Du GH (2007) Lectin-like oxidized low-density lipoprotein receptor-1: protein, ligands, expression and pathophysiological significance. Chin Med J 120:421–426PubMedGoogle Scholar
  12. Chen ST, Lin YL, Huang MT (2008) CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453:672–676PubMedCrossRefGoogle Scholar
  13. Chen S, Liu R, Wu M et al (2012) CLEC5A regulates Japanese encephalitis virus-induced neuroinflammation and lethality. PLoS Pathog 8, e1002655PubMedPubMedCentralCrossRefGoogle Scholar
  14. Chiba S, Ikushima H, Ueki H et al (2014) Recognition of tumor cells by Dectin-1 orchestrates innate immune cells for anti-tumor responses. eLife 3, e04177PubMedPubMedCentralCrossRefGoogle Scholar
  15. Coombs PJ, Graham SA, Drickamer K et al (2005) Selective binding of the scavenger receptor C-type lectin to Lewis(x) trisaccharide and related glycan ligands. J Biol Chem 280:22993–22999PubMedCrossRefGoogle Scholar
  16. Curtis BM, Scharnowske S, Watson AJ (1992) Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Proc Nat Acad Sci 89:8356–8360PubMedPubMedCentralCrossRefGoogle Scholar
  17. De Jong MA, Vriend LE, Theelen B et al (2010) C-type lectin Langerin is a beta-glucan receptor on human Langerhans cells that recognizes opportunistic and pathogenic fungi. Mol Immunol 47:1216–1225PubMedPubMedCentralCrossRefGoogle Scholar
  18. De Witte L, Nabatov A, Pion M et al (2007) Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat Med 13:367–371PubMedCrossRefGoogle Scholar
  19. Dominguez-Soto A, Aragoneses-Fenoll L, Martin-Gayo E et al (2007) The DC-SIGN-related lectin LSECtin mediates antigen capture and pathogen binding by human myeloid cells. Blood 109:5337–5345PubMedCrossRefGoogle Scholar
  20. Dong B, Li D, Li R et al (2014) A chitin-like component on sclerotic cells of Fonsecaea pedrosoi inhibits Dectin-1-mediated murine Th17 development by masking β-glucans. PLoS ONE 9, e114113PubMedPubMedCentralCrossRefGoogle Scholar
  21. Driessen NN, Ummels R, Maaskant JJ et al (2009) Role of phosphatidylinositol mannosides in the interaction between mycobacteria and DC-SIGN. Infect Immun 77:4538–4547PubMedPubMedCentralCrossRefGoogle Scholar
  22. Dzionek A, Sohma Y, Nagafune J et al (2001) BDCA-2, a novel plasmacytoid Dendritic Cell-specific Type II C-type Lectin, mediates antigen capture and is a potent inhibitor of interferon α/β Induction. J Exp Med 194:1823–1834PubMedPubMedCentralCrossRefGoogle Scholar
  23. Ehlers S (2010) DC-SIGN and mannosylated surface structures of Mycobacterium tuberculosis: a deceptive liaison. Eur J Cell Biol 89:95–101PubMedCrossRefGoogle Scholar
  24. Eriksson M, Johannssen T, von Smolinski D et al (2013) The C-Type lectin receptor SIGNR3 binds to fungi present in commensal microbiota and influences immune regulation in experimental colitis. Front Immunol 4:196PubMedPubMedCentralCrossRefGoogle Scholar
  25. Eriksson M, Serna S, Maglinao M et al (2014) Biological evaluation of multivalent LewisX-MGL-1 interactions. ChemBioChem 15:844–851PubMedCrossRefGoogle Scholar
  26. Feinberg H, Rowntree TJ, Tan SL et al (2013) Common polymorphisms in human langerin change specificity for glycan ligands. J Biol Chem 288:36762–36771PubMedPubMedCentralCrossRefGoogle Scholar
  27. Ferry A, Malik G, Guinchard X et al (2014) Synthesis and evaluation of di- and trimeric hydroxylamine-based β-(1→3)-glucan mimetics. J Am Chem Soc 136:14852–14857PubMedCrossRefGoogle Scholar
  28. Furukawa A, Kamishikiryo J, Mori D et al (2013) Structural analysis for glycolipid recognition by the C-type lectins Mincle and MCL. Proc Natl Acad Sci U S A 110:17438–17443PubMedPubMedCentralCrossRefGoogle Scholar
  29. Galustian C, Park CG, Chai W et al (2004) High and low affinity carbohydrate ligands revealed for murine SIGN-R1 by carbohydrate array and cell binding approaches, and differing specificities for SIGN-R3 and langerin. Int Immunol 16:853–866PubMedCrossRefGoogle Scholar
  30. Geijtenbeek TB, Groot PC, Nolte MA et al (2002) Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo. Blood 100:2908–2916PubMedCrossRefGoogle Scholar
  31. Geurtsen J, Chedammi S, Mesters J et al (2009) Identification of mycobacterial α-glucan as a novel ligand for DC-SIGN: involvement of mycobacterial capsular polysaccharides in host immune modulation. J Immunol 183:5221–5231PubMedCrossRefGoogle Scholar
  32. Gillotte KL, Hörkkö S, Witztum JL et al (2000) Oxidized phospholipids, linked to apolipoprotein B of oxidized LDL, are ligands for macrophage scavenger receptors. J Lipid Res 41:824–833PubMedGoogle Scholar
  33. Gramberg T, Hofmann H, Möller P et al (2005) LSECtin interacts with filovirus glycoproteins and the spike protein of SARS coronavirus. Virology 340:224–236PubMedCrossRefGoogle Scholar
  34. Hattori Y, Morita D, Fujiwara N et al (2014) Glycerol monomycolate is a novel ligand for the human, but not mouse macrophage inducible C-type lectin, Mincle. J Biol Chem 289:15405–15412PubMedPubMedCentralCrossRefGoogle Scholar
  35. Holla A, Skerra A (2011) Comparative analysis reveals selective recognition of glycans by the dendritic cell receptors DC-SIGN and langerin. Protein Eng Des Sel 24:659–669PubMedCrossRefGoogle Scholar
  36. Hsu TL, Cheng SC, Yang WB et al (2009) Profiling carbohydrate-receptor interaction with recombinant innate immunity receptor-Fc fusion proteins. J Biol Chem 284:34479–34489PubMedPubMedCentralCrossRefGoogle Scholar
  37. Iida S, Yamamoto K, Irimura T (1999) Interaction of human macrophage C-type lectin with O-linked N-acetylgalactosamine residues on mucin glycopeptides. J Biol Chem 274:10697–10705PubMedCrossRefGoogle Scholar
  38. Ishikawa E, Ishikawa T, Morita YS et al (2009) Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J Exp Med 206:2879–2888PubMedPubMedCentralCrossRefGoogle Scholar
  39. Ishikawa T, Itoh F, Yoshida S et al (2013) Identification of distinct ligands for the C-type lectin receptors Mincle and Dectin-2 in the pathogenic fungus Malassezia. Cell Host Microbe 13:477–488PubMedCrossRefGoogle Scholar
  40. Jono T, Miyazaki A, Nagai R et al (2002) Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) serves as an endothelial receptor for advanced glycation end products (AGE). FEBS Lett 511:170–174PubMedCrossRefGoogle Scholar
  41. Joyce-Shaikh B, Bigler ME, Cao CC et al (2010) Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis. J Exp Med 207:579–589PubMedPubMedCentralCrossRefGoogle Scholar
  42. Joyce-Shaikh B, Wilson DC, Cua DJ et al (2014) Mdl-1 Ligand. Patent WO20140227719Google Scholar
  43. Kakutani M, Masaki T, Sawamura T (2000) A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1. Proc Natl Acad Sci U S A 97:360–364PubMedPubMedCentralCrossRefGoogle Scholar
  44. Kaneko MK, Kato Y, Kameyama A et al (2007) Functional glycosylation of human podoplanin: glycan structure of platelet aggregation-inducing factor. FEBS Lett 581:331–336PubMedCrossRefGoogle Scholar
  45. Kang YS, Yamazaki S, Iyoda T et al (2003) SIGN-R1, a novel C-type lectin expressed by marginal zone macrophages in spleen, mediates uptake of the polysaccharide dextran. Int Immunol 15:177–186PubMedCrossRefGoogle Scholar
  46. Kang PB, Azad AK, Torrelles JB et al (2005) The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis. J Exp Med 202:987–999PubMedPubMedCentralCrossRefGoogle Scholar
  47. Kato Y, Kaneko MK, Kunita A et al (2008) Molecular analysis of the pathophysiological binding of the platelet aggregation-inducing factor podoplanin to the C-type lectin-like receptor CLEC-2. Cancer Sci 99:54–61PubMedGoogle Scholar
  48. Khan AA, Chee SH, McLaughlin RJ et al (2011) Long-chain lipids are required for the innate recognition of trehalose diesters by macrophages. ChemBioChem 12:2572–2576PubMedCrossRefGoogle Scholar
  49. Khan AA, Kamena F, Timmer MS et al (2013) Development of a benzophenone and alkyne functionalised trehalose probe to study trehalose dimycolate binding proteins. Org Biomol Chem 11:881–885PubMedCrossRefGoogle Scholar
  50. Kim HJ, Brennan PJ, Heaslip D et al (2015) Carbohydrate-dependent binding of langerin to SodC, a cell wall glycoprotein of Mycobacterium leprae. J Bacteriol 197:615–625PubMedPubMedCentralCrossRefGoogle Scholar
  51. Kodar K, Eising S, Khan AA et al (2015) The uptake of Trehalose glycolipids by macrophages is independent of Mincle. ChemBioChem 16:683–693PubMedCrossRefGoogle Scholar
  52. Koppel EA, Ludwig IS, Appelmelk BJ et al (2005) Carbohydrate specificities of the murine DC-SIGN homologue mSIGNR1. Immunobiology 210:195–201PubMedCrossRefGoogle Scholar
  53. Kumamoto Y, Linehan M, Weinstein JS et al (2013) CD301b+ dermal dendritic cells drive T helper 2 cell-mediated immunity. Immunity 39:733–743PubMedCrossRefGoogle Scholar
  54. Lahoud MH, Ahmet F, Zhang JG et al (2012) DEC-205 is a cell surface receptor for CpG oligonucleotides. Proc Natl Acad Sci U S A 109:16270–16275PubMedPubMedCentralCrossRefGoogle Scholar
  55. Lambert AA, Gilbert C, Richard M et al (2008) The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways. Blood 112:1299–1307PubMedPubMedCentralCrossRefGoogle Scholar
  56. Laskarin G, Redzovic A, Vlastelic I et al (2011) Tumor-associated glycoprotein (TAG-72) is a natural ligand for the C-type lectin-like domain that induces anti-inflammatory orientation of early pregnancy decidual CD1a+ dendritic cells. Am J Reprod Immunol 88:12–23CrossRefGoogle Scholar
  57. Layzer JM, Mahanty SK, Redick CC et al (2010) Nucleic acid modulators of CLEC-2. Patent WO2012051571Google Scholar
  58. Lee RT, Hsu TL, Huang SK et al (2011) Survey of immune-related, mannose/fucose-binding C-type lectin receptors reveals widely divergent sugar-binding specificities. Glycobiology 21:512–520PubMedPubMedCentralCrossRefGoogle Scholar
  59. Lefèvre L, Lugo-Villarino G, Meunier E et al (2013) The C-type lectin receptors Dectin-1, MR, and SIGNR4 contribute both positively and negatively to the macrophage response to Leishmania infantum. Immunity 38:1038–1049PubMedCrossRefGoogle Scholar
  60. Leteux C, Chai W, Loveless RW et al (2000) The cysteine-rich domain of the macrophage mannose receptor is a multispecific lectin that recognizes chondroitin sulfates A and B and sulfated oligosaccharides of blood group Lewisa and Lewisx types in addition to the sulfated N-glycans of lutropin. J Exp Med 191:1117–1126PubMedPubMedCentralCrossRefGoogle Scholar
  61. Li X, Wang J, Wang W et al (2013) Immunomodulatory activity of a novel, synthetic beta-glucan (β-glu6) in murine macrophages and human peripheral blood mononuclear cells. PLoS ONE 8, e80399PubMedPubMedCentralCrossRefGoogle Scholar
  62. Lightfoot YL, Selle K, Yang T et al (2015) SIGNR3-dependent immune regulation by lactobacillus acidophilus surface layer protein A in colitis. EMBO J 34:881–895PubMedCrossRefGoogle Scholar
  63. Liu W, Tang L, Zhang G et al (2004) Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem 279:18748–18758PubMedCrossRefGoogle Scholar
  64. Lu J, Yang JH, Burns AR et al (2009) Mediation of electronegative low-density lipoprotein signaling by LOX-1: a possible mechanism of endothelial apoptosis. Circ Res 104:619–627PubMedCrossRefGoogle Scholar
  65. Maeda N, Nigou J, Herrmann JL et al (2003) The cell surface receptor DC-SIGN discriminates between mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J Biol Chem 278:5513–5516PubMedCrossRefGoogle Scholar
  66. Maglinao M, Eriksson M, Schlegel MK et al (2014) A platform to screen for C-type lectin receptor-binding carbohydrates and their potential for cell-specific targeting and immune modulation. J Control Release 175:36–42PubMedCrossRefGoogle Scholar
  67. Manne BK, Getz TM, Hughes CE et al (2013) Fucoidan is a novel platelet agonist for the C-type lectin-like receptor 2 (CLEC-2). J Biol Chem 288:7717–7726PubMedPubMedCentralCrossRefGoogle Scholar
  68. Marsche G, Levak-Frank S, Quehenberger O et al (2001) Identification of the human analog of SR-BI and LOX-1 as receptors for hypochlorite-modified high-density lipoprotein on human umbilical venous endothelial cells. FASEB J 15:1095–1097PubMedGoogle Scholar
  69. Martinelli E, Cicala C, Van Ryk D et al (2007) HIV-1 gp120 inhibits TLR9-mediated activation and IFN-γ secretion in plasmacytoid dendritic cells. Proc Natl Acad Sci U S A 104:3396–3401PubMedPubMedCentralCrossRefGoogle Scholar
  70. Martinez-Pomares L (2012) The mannose receptor. J Leukoc Biol 92:1177–1186PubMedCrossRefGoogle Scholar
  71. McGreal EP, Rosas M, Brown GD et al (2006) The carbohydrate-recognition domain of Dectin-2 is a C-type lectin with specificity for high mannose. Glycobiology 16:422–430PubMedCrossRefGoogle Scholar
  72. Meyer S, Van Liempt E, Imberty A et al (2005) DC-SIGN mediates binding of dendritic cells to authentic pseudo-LewisY glycolipids of Schistosoma mansoni cercariae, the first parasite-specific ligand of DC-SIGN. J Biol Chem 280:37349–37359PubMedCrossRefGoogle Scholar
  73. Miszczyk E, Rudnicka K, Moran AP et al (2012) Interaction of Helicobacter pylori with C-type lectin dendritic cellspecific ICAM grabbing nonintegrin. J Biomed Biotechnol 2012, Article ID 206463, 10 ppGoogle Scholar
  74. Mitchell DA, Fadden AJ, Drickamer K (2001) A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR: subunit organization and binding to multivalent ligands. J Biol Chem 276:28939–28945PubMedCrossRefGoogle Scholar
  75. Miyake Y, Toyonaga K, Mori D et al (2013) C-type lectin MCL is an FcRγ-coupled receptor that mediates the adjuvanticity of mycobacterial cord factor. Immunity 38:1050–1062PubMedCrossRefGoogle Scholar
  76. Moriwaki H, Kume N, Sawamura T et al (1998) Ligand specificity of LOX-1, a novel endothelial receptor for oxidized low density lipoprotein. Arterioscler Thromb Vasc Biol 18:1541–1547PubMedCrossRefGoogle Scholar
  77. Mortezai N, Behnken HN, Kurze AK et al (2013) Tumor-associated Neu5Ac-Tn and Neu5Gc-Tn antigens bind to C-type lectin CLEC10A (CD301, MGL). Glycobiology 23:844–852PubMedCrossRefGoogle Scholar
  78. Mullin NP, Hall KT, Taylor ME (1994) Characterization of ligand binding to a carbohydrate-recognition domain of the macrophage mannose receptor. J Biol Chem 269:28405–28413PubMedGoogle Scholar
  79. Muñoz-García JC, Chabrol E, Vivès RR et al (2015) Langerin-heparin interaction: two binding sites for small and large ligands as revealed by a combination of NMR spectroscopy and cross-linking mapping experiments. J Am Chem Soc 137:4100–4110PubMedCrossRefGoogle Scholar
  80. Murshid A, Theriault J, Gong J et al (2011) Investigating receptors for extracellular heat shock proteins. Methods Mol Biol 787:289–302PubMedPubMedCentralCrossRefGoogle Scholar
  81. Nagae M, Yamanaka K, Hanashima S et al (2013) Recognition of bisecting N-acetylglucosamine: structural basis for asymmetric interaction with the mouse lectin dendritic cell inhibitory receptor 2. J Biol Chem 288:33598–33610PubMedPubMedCentralCrossRefGoogle Scholar
  82. Neumann K, Castiñeiras-Vilariño M, Höckendorf U et al (2014) CLEC12a is an inhibitory receptor for uric acid crystals that regulates inflammation in response to cell death. Immunology 40:389–399Google Scholar
  83. Ng WC, Liong S, Tate MD et al (2014) The macrophage galactose-type lectin can function as an attachment and entry receptor for influenza virus. J Virol 88:1659–1672PubMedPubMedCentralCrossRefGoogle Scholar
  84. Oka K, Sawamura T, Kikuta KI et al (1998) Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci U S A 95:9535–9540PubMedPubMedCentralCrossRefGoogle Scholar
  85. Okamura T, Sekikawa A, Sawamura T et al (2013) LOX-1 ligands containing apolipoprotein B and carotid intima-media thickness in middle-aged community-dwelling US Caucasian and Japanese men. Atherosclerosis 229:240–245PubMedPubMedCentralCrossRefGoogle Scholar
  86. Palma AS, Feizi T, Zhang Y et al (2006) Ligands for the β-glucan receptor, Dectin-1, assigned using “designer” microarrays of oligosaccharide probes (neoglycolipids) generated from glucan polysaccharides. J Biol Chem 281:5771–5779PubMedCrossRefGoogle Scholar
  87. Picco G, Beatson R, Taylor-Papadimitriou J et al (2014) Targeting DNGR-1 (CLEC9A) with antibody/MUC1 peptide conjugates as a vaccine for carcinomas. Eur J Immunol 44:1947–1955PubMedPubMedCentralCrossRefGoogle Scholar
  88. Plato A, Willment JA, Brown GD (2013) C-Type lectin-like receptors of the Dectin-1 cluster: ligands and signalling pathways. Int Rev Immunol 32:134–156PubMedPubMedCentralCrossRefGoogle Scholar
  89. Powlesland AS, Ward EM, Sadhu SK et al (2006) Widely divergent biochemical properties of the complete set of mouse DC-SIGN-related proteins. J Biol Chem 281:20440–20449PubMedCrossRefGoogle Scholar
  90. Pyż E, Huysamen C, Marshall ASJ et al (2008) Characterisation of murine MICL (CLEC12A) and evidence for an endogenous ligand. Eur J Immunol 38:1157–1163PubMedPubMedCentralCrossRefGoogle Scholar
  91. Rappleye CA, Groppe Eissenberg L, Goldman WE (2007) Histoplasma capsulatum α-(1,3)-glucan blocks innate immune recognition by the β-glucan receptor. Proc Natl Acad Sci 104:1366–1370PubMedPubMedCentralCrossRefGoogle Scholar
  92. Riboldi E, Daniele R, Parola C et al (2011) Human C-type lectin domain family 4, member C (CLEC4C/BDCA-2/CD303) is a receptor for asialo-galactosyl-oligosaccharides. J Biol Chem 286:35329–35333PubMedPubMedCentralCrossRefGoogle Scholar
  93. Ritter M, Gross O, Kays S et al (2010) Schistosoma mansoni triggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses. Proc Natl Acad Sci U S A 107:20459–20464PubMedPubMedCentralCrossRefGoogle Scholar
  94. Rothfuchs AG, Bafica A, Feng CG et al (2007) Dectin-1 interaction with Mycobacterium tuberculosis leads to enhanced IL-12p40 production by splenic dendritic cells. J Immunol 179:3463–3471PubMedCrossRefGoogle Scholar
  95. Saba K, Denda-Nagai K, Irimura T (2009) A C-type lectin MGL1/CD301a plays an anti-inflammatory role in murine experimental colitis. Am J Pathol 174:144–152PubMedPubMedCentralCrossRefGoogle Scholar
  96. Sabatte J, Faigle W, Ceballos A et al (2011) Semen clusterin is a novel DC-SIGN ligand. J Immunol 187:5299–5309PubMedCrossRefGoogle Scholar
  97. Saijo S, Ikeda S, Yamebe K et al (2010) Dectin-2 recognition of α-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity 32:681–691PubMedCrossRefGoogle Scholar
  98. Sancho D, Reis e Sousa C (2012) Signalling by myeloid C-type lectin receptors in immunity and homeostasis. Annu Rev Immunol 30:491–529PubMedPubMedCentralCrossRefGoogle Scholar
  99. Sato K, Yang XI, Yudate T et al (2006) Dectin-2 is a pattern recognition receptor for fungi that couples with the Fc receptor γ chain to induce innate immune responses. J Biol Chem 281:38854–38866PubMedCrossRefGoogle Scholar
  100. Sawamura T, Kume N, Aoyama T et al (1997) An endothelial receptor for oxidized low-density lipoprotein. Nature 386:73–77PubMedCrossRefGoogle Scholar
  101. Scarpellino L, Oeschger F, Guillaume P (2007) Interactions of Ly49 family receptors with MHC class I ligands in trans and cis. J Immunol 178:1277–1284PubMedCrossRefGoogle Scholar
  102. Schoenen H, Bodendorfer B, Hitchens K et al (2010) Cutting edge: mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate. J Immunol 184:2756–2760PubMedPubMedCentralCrossRefGoogle Scholar
  103. Shepherd VL, Lee YC, Schlesinger PH et al (1981) L-Fucose-terminated glycoconjugates are recognized by pinocytosis receptors on macrophages. Proc Nat Acad Sci 78:1019–1022PubMedPubMedCentralCrossRefGoogle Scholar
  104. Shi X, Niimi S, Ohtani T et al (2001) Characterization of residues and sequences of the carbohydrate recognition domain required for cell surface localization and ligand binding of human lectin-like oxidized LDL receptor. J Cell Sci 114:1273–1282PubMedGoogle Scholar
  105. Shih HH, Zhang S, Cao W et al (2009) CRP is a novel ligand for the oxidized LDL receptor LOX-1. Am J Physiol Heart Circ Physiol 296:H1643–H1650PubMedCrossRefGoogle Scholar
  106. Shimaoka T, Kume N, Minami M et al (2001) LOX-1 supports adhesion of Gram-positive and Gram-negative bacteria. J Immunol 166:5108–5114PubMedCrossRefGoogle Scholar
  107. Shrimpton RE, Butler M, Morel AS et al (2009) CD205 (DEC-205): a recognition receptor for apoptotic and necrotic self. Mol Immunol 46:1229–1239PubMedPubMedCentralCrossRefGoogle Scholar
  108. Singh SK, Streng-Ouwehand I, Litjens M et al (2009) Characterization of murine MGL1 and MGL2 C-type lectins: distinct glycan specificities and tumor binding properties. Mol Immunol 46:1240–1249PubMedCrossRefGoogle Scholar
  109. Singh SK, Streng-Ouwehand I, Litjens M et al (2011) Tumour-associated glycan modifications of antigen enhance MGL2 dependent uptake and MHC class I restricted CD8 T cell responses. Int J Cancer 128:1371–1383PubMedCrossRefGoogle Scholar
  110. Srivastava L, Tundup S, Choi BS et al (2014) Immunomodulatory glycan lacto-N-fucopentaose III requires clathrin-mediated endocytosis to induce alternative activation of antigen-presenting cells. Infect Immun 82:1891–1903PubMedPubMedCentralCrossRefGoogle Scholar
  111. Stahl P, Schlesinger PH, Rodman JS et al (1976) Recognition of lysosomal glycosidases in vivo inhibited by modified glycoproteins. Nature 264:86–88PubMedCrossRefGoogle Scholar
  112. Stambach NS, Taylor ME (2003) Characterization of carbohydrate recognition by langerin, a C-type lectin of Langerhans cells. Glycobiology 13:401–410PubMedCrossRefGoogle Scholar
  113. Stocker BL, Khan AA, Chee SH et al (2014) On one leg: trehalose monoesters activate macrophages in a Mincle-dependent manner. ChemBioChem 15:382–388PubMedCrossRefGoogle Scholar
  114. Suzuki N, Yamamoto K, Toyoshima S et al (1996) Molecular cloning and expression of cDNA encoding human macrophage C-type lectin. Its unique carbohydrate binding specificity for Tn antigen. J Immunol 156:128–135PubMedGoogle Scholar
  115. Suzuki-Inoue K, Kato Y, Inoue O et al (2007) Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 282:25993–26001PubMedCrossRefGoogle Scholar
  116. Suzuki-Inoue K, Inoue O, Ozaki Y (2011) Novel platelet activation receptor CLEC-2: from discovery to prospects. J Thromb Haemost 9(Suppl 1):44–55PubMedCrossRefGoogle Scholar
  117. Tai LH, Goulet ML, Belanger S et al (2007) Recognition of H-2Kb by Ly49Q suggests a role for class Ia MHC regulation of plasmacytoid dendritic cell function. Mol Immunol 44:2638–2646PubMedCrossRefGoogle Scholar
  118. Takahara K, Yashima Y, Omatsu Y et al (2004) Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and Langerin, C-type lectins. Int Immunol 16:819–829PubMedCrossRefGoogle Scholar
  119. Tanne A, Ma B, Boudou F et al (2009) A murine DC-SIGN homologue contributes to early host defense against Mycobacterium tuberculosis. J Exp Med 206:2205–2220PubMedPubMedCentralCrossRefGoogle Scholar
  120. Tateno H, Ohnishi K, Yabe R et al (2010) Dual specificity of Langerin to sulfated and mannosylated glycans via a single C-type carbohydrate recognition domain. J Biol Chem 285:6390–6400PubMedPubMedCentralCrossRefGoogle Scholar
  121. Taylor ME, Bezouska K, Drickamer K (1992) Contribution to ligand binding by multiple carbohydrate-recognition domains in the macrophage mannose receptor. J Biol Chem 267:1719–1726PubMedGoogle Scholar
  122. Terrazas CA, Alcántara-Hernández M, Bonifaz L et al (2013) Helminth-excreted/secreted products are recognized by multiple receptors on DCs to block the TLR response and bias Th2 polarization in a cRAF dependent pathway. FASEB J 27:4547–4560PubMedPubMedCentralCrossRefGoogle Scholar
  123. Thiagarajan PS, Yakubenko VP, Elsori DH et al (2013) Vimentin is an endogenous ligand for the pattern recognition receptor Dectin-1. Cardiovasc Res 99:494–504PubMedPubMedCentralCrossRefGoogle Scholar
  124. Tsuiji M, Fujimori M, Ohashi Y et al (2002) Molecular cloning and characterization of a novel mouse macrophage C-type lectin, mMGL2, which has a distinct carbohydrate specificity from mMGL1. J Biol Chem 277:28892–28901PubMedCrossRefGoogle Scholar
  125. Upham JP, Pickett D, Irimura T et al (2010) Macrophage receptors for influenza A virus: role of the macrophage galactose-type lectin and mannose receptor in viral entry. J Virol 84:3730–3737PubMedPubMedCentralCrossRefGoogle Scholar
  126. Van der Peet PL, Gunawan C, Torigoe S et al (2015) Corynomycolic acid-containing glycolipids signal through the pattern recognition receptor Mincle. Chem Commun 51:5100–5103CrossRefGoogle Scholar
  127. Van Die I, Van Vliet SJ, Nyame AK et al (2003) The dendritic cell-specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis x. Glycobiology 13:471–478PubMedCrossRefGoogle Scholar
  128. Van Kooyk Y, Ilarregui JM, Van Vliet SJ (2015) Novel insights into the immunomodulatory role of the dendritic cell and macrophage-expressed C-type lectin MGL. Immunobiology 220:185–192PubMedCrossRefGoogle Scholar
  129. Van Vliet SJ, Van Liempt E, Saeland E et al (2005) Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells. Int Immunol 17:661–669PubMedCrossRefGoogle Scholar
  130. Vázquez A, Ruiz-Rosado Jde D, Terrazas LI et al (2014) Mouse macrophage galactose-type lectin (mMGL) is critical for host resistance against Trypanosoma cruzi infection. Int J Biol Sci 10:909–920PubMedPubMedCentralCrossRefGoogle Scholar
  131. Wells CA, Salvage-Jones JA, Li X et al (2008) The Macrophage-inducible C-type lectin, Mincle, is an essential component of the innate immune response to Candida albicans. J Immunol 180:7404–7413PubMedCrossRefGoogle Scholar
  132. Yadav M, Schorey JS (2006) The β-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 108:3168–3175PubMedPubMedCentralCrossRefGoogle Scholar
  133. Yamasaki S, Ishikawa E, Sakuma M et al (2008) Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol 9:1179–1188PubMedCrossRefGoogle Scholar
  134. Yamasaki S, Matsumoto M, Takeuchi O et al (2009) C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. Proc Natl Acad Sci U S A 106:1897–1902PubMedPubMedCentralCrossRefGoogle Scholar
  135. Yang K, Park CG, Cheong C et al (2015) Host Langerin (CD207) is a receptor for Yersinia pestis phagocytosis and promotes dissemination. Immunol Cell Biol 93:815–24PubMedPubMedCentralCrossRefGoogle Scholar
  136. Yonekawa A, Saijo S, Hoshino Y et al (2014) Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of Mycobacteria. Immunity 41:402–413PubMedCrossRefGoogle Scholar
  137. Yoshimoto R, Fujita Y, Kakino A et al (2011) The discovery of LOX-1, its ligands and clinical significance. Cardiovasc Drugs Ther 25:379–391PubMedPubMedCentralCrossRefGoogle Scholar
  138. Zhang SS, Park C, Zhang P et al (2008) Plasminogen activator Pla of Yersinia pestis utilizes murine DEC-205 (CD205) as a receptor to promote dissemination. J Biol Chem 283:31511–31521PubMedPubMedCentralCrossRefGoogle Scholar
  139. Zhang JG, Czabotar PE, Policheni AN et al (2012) The dendritic cell receptor CLEC9A binds damaged cells via exposed actin filaments. Immunity 36:646–657PubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Amy J. Foster
    • 1
  • Jessie H. Bird
    • 1
  • Mattie S. M. Timmer
    • 1
  • Bridget L. Stocker
    • 1
    Email author
  1. 1.School of Chemical and Physical SciencesVictoria University of WellingtonWellingtonNew Zealand

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