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Dual function of C-type lectin-like receptors in the immune system

Alessandra Cambi and Carl G Figdor
Carbohydrate-binding C-type lectin and lectin-like receptors play an important role in the immune system. The large family can be subdivided into subtypes according to their structural similarities and functional differences. The selectins are of major importance in mediating cell adhesion and migration, and the mannose receptor subfamily is specialised in the binding and uptake of pathogens. Recent advances show that some of the type II C-type lectin-like receptors, such as DC-SIGN, can function both as an adhesion receptor and as a phagocytic pathogen-recognition receptor, similar to the Toll-like receptors. Although major differences in the cytoplasmic domains of these receptors might predict their function, recent ndings show that differences in glycosylation of ligands can dramatically alter C-type lectin-like receptor usage.
Addresses Department of Tumor Immunology, Nijmegen Center for Molecular Life Sciences, NCMLS/187 TIL, Postbox 9101, 6500HB Nijmegen, The Netherlands e-mail: c.gdor@ncmls.kun.nl

lectin or lectin-like receptors [1,2]. Many of these lectins are members of the Ca2-dependent C-type lectin family (Table 1) and recognise their ligands through the structurally related Ca2-dependent carbohydrate-recognition domains (CRDs). A well-dened subset the selectins primarily function as cell adhesion receptors that play an important role in homing of leukocytes. The binding specicity of selectin cell adhesion molecules results from an extended binding site within a single CRD. While cellcell contact by recognition of endogenous ligands is a prominent function of both selectins and lectin-like natural killer (NK) receptors (not discussed here), others are specialised in recognition of pathogens and therefore resemble the ancient pattern-recognition molecules the Toll-like receptor (TLR) family that are thought to recognise foreign ligands during the early phases of the immune response. In this review, we will discuss differences between TLRs and LLRs (see also Box 1). Pathogen recognition by soluble collectins such as serum mannose-binding protein and pulmonary surfactant proteins, but also the macrophage cell-surface mannose receptor, is effected by binding of terminal monosaccharide residues characteristic of bacterial and fungal cell surfaces. The broad selectivity of the monosaccharidebinding site and the geometrical arrangement of multiple CRDs in the intact lectins might explain their ability to mediate discrimination between self and non-self. We shall discuss several novel LLRs that have been found recently, some of which are expressed by macrophages and dendritic cells (DCs) and play a role both as a cell-adhesion receptor and as a phagocytic pathogen-recognition receptor (PRR). Finally, we shall discuss the importance of ligand glycosylation with respect to recognition by LLRs.

Current Opinion in Cell Biology 2003, 15:539546 This review comes from a themed issue on Cell-to-cell contact and extracellular matrix Edited by Eric Brown and Elisabetta Dejana 0955-0674/$ see front matter 2003 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2003.08.004

Abbreviations CRD carbohydrate-recognition domain DC dendritic cell DC-SIGN DC-specic ICAM-3-grabbing non-integrin EC endothelial cell GlyCAM-1 glycosylation-dependent cell adhesion molecule 1 HEV high endothelial venule ICAM intercellular adhesion molecule IFN interferon LLR lectin-like receptor LSEC liver sinusoidal EC MMR macrophage mannose receptor PAMP pathogen-associated molecular pattern PRR pathogen-recognition receptor sLeX sialyl Lewis X TLR Toll-like receptor

C-type lectin-like receptors in leukocyte trafcking

The selectins a family comprising three members (E-, L- and P-selectin) form the prototype C-type LLRs that mediate adhesion and homing to the peripheral tissues. Both E- and P selectin are expressed on activated endothelium and play a major role in lymphocyte extravasation (Figure 1). Sialyl-Lewis X (sLeX) is the predominant carbohydrate recognised by E- or P-selectin. GlyCAM-1 (glycosylation-dependent cell adhesion molecule 1) and CD34, expressed at low levels on endothelium, can bind to L-selectin. More recently, LOX-1, originally identied as an endothelial scavenger receptor with a C-type LLR
Current Opinion in Cell Biology 2003, 15:539546

Introduction
Cells of the immune system are equipped with many lectin and lectin-like receptors (LLRs, carbohydrate-binding proteins) many of which are of eminent importance for their function. During the past two years, genomic approaches to dene leukocytes in more molecular terms have led to the identication of a series of genes that encode
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540 Cell-to-cell contact and extracellular matrix

Table 1 Overview of structural and functional relationships of subfamilies of C-type lectin-like receptors. Group and molecular structure VI. MMR family C-type lectin Localisation Ligand specificity Mannose, fucose, sLeX ? Collagen Function Cytoplasmic tail motif (single letter amino acid code) FENTLY FSSVRY FEGARY EDE

MMR DEC-205 Endo180

DCs, LC, Mo, Mf, LE DMECs DCs, LC, tEC, fibroblasts DCs, LC DCs DCs vEC, Mf

Antigen uptake, cell adhesion Antigen uptake ECM degradation

V. NK receptors
-ss-

b-GR (dectin-1) CLEC-1 CLEC-2 LOX-1

b-Glucan ? ? ox-LDL, AGE, aPL

Antigen uptake, cell adhesion ? ? Phagocytosis

YTQL YSST YITL

DED DDD

II. Type II receptors

DC-SIGN DC-SIGN receptor DCIR Langerin DCAL-1 BDCA-2

DCs, HC, dMf, aMf LSE, LNsE, pcE DCs, Mo, Mf, PMN, B LC DCs, germinal centre B Plasmacytoid DCs Leukocytes Platelets, endothelium Activated endothelium

Mannan, LeX, fucose Mannan ? ? ? ? s6SLeX sLe , s6SLe sLeX, s6SLeX

X X

Antigen uptake, cell adhesion Antigen uptake ? Birbeck granules format T cell co-stimulation Antigen uptake? Leukocytes tethering: homing and inflammation

YKSL LL LL ITYAEV

EEE EED

EEE

IV. Selectins

L-selectin P-selectin E-selectin

YGVF KKFV YQKP

Blue sphere, C-type lectin domain; green rectangle, fibronectin type II repeat; orange oval, Complement regulatory domain; blue oval, epidermal growth factor (EGF)-like domain. Based on nomenclature from A genomics resource for animal lectins, URL http://ctld.glycob.ox.ac.uk. AGE, advanced glycation end-products; aPL, anionic phospholipids; B, B cells; DCAL-1, DC-associated lectin-1; DCIR, DC immunoreceptor; DMEC, dermal microvascular ECs; ECM, extracellular matrix; b-GR, b-glucan receptor; HC, Hofbauer cells; LC, Langerhans cells; LE, lymphatic endothelium; LNsE, lymph node sinuses endothelium; LSE, liver sinusoidal endothelium; Mf, d(decidual), a(alveolar) macrophages; Mo, monocytes; NK, natural killer; ox-LDL, oxidised low-density lipoprotein; pcE, placental capillary endothelium; PMN, polymorphic nuclear cells; s6SLeX, sialyl 6-sulpho LewisX; tEC, thymic ECs; vEC, vascular ECs.

structure, was shown to support rolling and adhesion of mononuclear leukocytes [3] and platelets [4] to endothelium. As such, LOX-1 plays an important role in leukocyte extravasation upon inammatory stimuli [5].
Box 1 Similarities and differences between C-type LLRs and
TLRs.  Both are PRRs, recognising PAMPs  Both play an important role in the innate immune system  Whereas TLRs are mainly involved in activation of cells of the immune system, the function of LLRs is pleiotropic. As well as recognition of PAMPs and subsequent phagocytosis of pathogens, LLRs can recognise endogenous ligands and mediate cellcell contact and homing  TLRs can discriminate between self and non-self, LLRs cannot  LLRs recognise carbohydrate structures; ligands of TLRs comprise, in addition to carbohydrates, peptidoglycans, unmethylated CpG motifs of bacterial DNA or double-stranded RNA of viruses  The cytoplasmic domains of most TLRs are highly conserved, that of LLRs are highly variable, depending on their primary function Whereas TLR signalling through MyD88 and IRAK resulting in activation of NF-kB is partially resolved, LLR signalling remains obscure

Similarly, the macrophage mannose receptor (MMR) parallels members of the selectin family. Through its cysteinerich domain, MMR can bind to other macrophages in marginal zones of the spleen, and to B cells in germinal centres. This is thought to direct MMR-bearing cells toward germinal centres during an immune response. The nding that several classes of carbohydrate bind MMR provides a mechanism for regulating the trafcking and function of MMR-bearing cells [6]. Recently, MMR was identied on human lymphatic endothelium to mediate binding of lymphocytes through L-selectin [7]. Interestingly, MMR is absent on high endothelial venules (HEVs), indicating that L-selectin exploits distinct ligands to mediate binding at sites of lymphocyte entrance and exit within lymph nodes. Dermal microvascular endothelial cells (DMECs) also express MMR [8] and this has been associated with the scavenger function of MMR, thus providing a rst example of the dual function for an LLR (Figure 1). Further evidence for a role of C-type lectins in trafcking of DCs comes from the observation that intercellular adhesion molecule 2 (ICAM-2), constitutively expressed
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Dual function of C-type lectin-like receptors in the immune system Cambi and Figdor 541

Figure 1

Cell adhesion, homing, co-stimulation

Pathogen recognition, endocytosis MMR DEC-205 DC-SIGN Viruses HIV-1 Ebola CMV Dengue Hepatitis C Bacteria Mycobacterium Helicobacter Parasites Leishmania Schistosoma Fungi Candida
DC -S IG N

T cell

ICAM-3 ?

DC-SIGN DCAL-1

L-selectin PSGL-1
LPS sele M GL ctin M -1 R

DC

TLR-7 TLR-9

TLR-2 TLR-4

eli

um

M P- R s E- ele CD sele ctin -3 ctin 4

do

th

LO X-

En

IC

AM

-2

Current Opinion in Cell Biology

The dual function of C-type LLRs in the immune system: pathogen recognition and cell adhesion. LLRs and TLRs share their function as pathogen-recognition receptors, but each has a different outcome. TLR-mediated pathogen recognition (through TLR-2, -4) results in direct leukocyte activation through recently defined signalling cascades (not shown but represented by yellow lightening symbols); ligand binding by several LLRs (MMR, DEC-205, DC-SIGN) results in endocytosis of the pathogen. How signals from TLRs and LLRs can synergise is currently unknown, but it is hypothesised that upon endocytosis of pathogens mediated by LLRs, fusion of late endosomes/lysosomes might lead to signalling when fused with intracellularly expressed TLRs (TLR-7, -9). Other LLRs (selectins, DCAL-1, DC-SIGN, MMR) have an important function in mediating contact (DCT-cell contact, T cell activation/co-stimulation) between leukocytes and the endothelium (homing). Some LLRs can function both as a cell adhesion receptor and as an endocytic receptor (DC-SIGN, MMR). Yellow spheres represent the endocytic pathway; orange sphere symbolises cytoplasmic compartments, as yet uncharacterised, that contain TLR-7 and -9.

by endothelium supports tethering and rolling of cells expressing DC-specic ICAM-3-grabbing non-integrin (DC-SIGN) [9]. DC-SIGNICAM-2 interactions regulate chemokine-induced transmigration of DCs across both resting and activated endothelium in vitro, indicating that DC-SIGN next to its capacity to bind pathogens [10] such as HIV-1 is central to this unusual trafcking capacity of DCs [9,11].

early, antigen-nonspecic contact between DCs and T cells, enabling T-cell receptor engagement by stabilisation of the DCT-cell contact zone [12]. Interestingly, two other C-type lectin-like receptors, dectin-1 [13] and DC-associated lectin-1 (DCAL-1) [14], both expressed by macrophages and DCs, have been proposed also to bind T cells. His-tagged fusion proteins of both proteins bind to the surface of T cells and promote their proliferation in the presence of anti-CD3 antibodies. This suggests that dectin-1 and DCAL-1 on DCs bind to as yet undened cellular ligands or carbohydrates on T cells, thereby delivering T cell co-stimulatory signals.

Antigen-presenting-cellT-cell interactions
Proliferation of leukocytes after antigenic stimulation is always associated with dense antigen-presenting cell (APC)T-cell clusters. There is increasing evidence that C-type LLR-mediated interactions are of importance here also. We have previously shown that DC-SIGN, highly expressed on DCs, binds ICAM-3 and mediates transient adhesion of DCs with T cells [12]. DC-SIGN supports
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Antigen uptake by C-type lectin-like receptors

Several C-type LLRs also participate in pathogen recognition and uptake. As well as the classical MMR, which is known to act as an endocytic receptor, DEC-205 [15],
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542 Cell-to-cell contact and extracellular matrix

BDCA-2 [16] and DC-SIGN [17,18] have also recently been shown to mediate antigen uptake. Whereas the MMR delivers antigen to the early endosomes and recycles to the surface, DEC-205, BDCA-2 and DCSIGN deliver antigens to late endosomes or lysosomes, where they are degraded. As well as the tyrosine-based coated pit sequence-uptake motif present in MMR (YXXZ or FXXXXY, where X can be any amino acid and Z denotes any amino acid with a bulky hydrophobic sidechain; Table 1), the cytoplasmic domains of DEC205, BDCA-2, CLEC-1 and DC-SIGN contain an additional triacidic cluster (EEE or DDD), important for targeting to proteolytic vacuoles [15]. Furthermore, a di-leucine motif (Table 1), present in the cytoplasmic domain of DC-SIGN, is essential for internalisation [17]. The liver sinusoidal endothelial-cell-associated homologue of DC-SIGN designated L-SIGN has the same ligand-binding specicities as DC-SIGN [19], but instead is not expressed by DCs. Liver sinusoids are specialised capillary vessels characterised by the presence of resident macrophages adhering to the liver sinusoidal endothelial cells (LSECs). LSECleukocyte interactions, which require expression of adhesion molecules on the cell surfaces, appear to constitute a central mechanism of peripheral immune surveillance in the liver. MMR, and now also L-SIGN, are known to be expressed on LSECs and might mediate the clearance of many potentially antigenic proteins from the circulation, in a manner similar to DCs in lymphoid organs.

Evidence is emerging that LLRs not only play a role as phagocytic PRRs; they also might synergise or antagonise TLR signals [24,25]. How they do this is currently unclear, however. For example, both TLR-4 and several LLRs bind fungi. Dectin-1, the b-glucan receptor, mediates attachment and uptake of fungi, exploiting its immunoreceptor tyrosine-based activation motif (ITAM). Although b-glucan is expressed by many fungi, live pathogenic strains such as Candida albicans lack b-glucan on their surface and thus bind poorly to dectin-1. By contrast, Candida albicans binds well to MMR [26,27] and DC-SIGN [28], recognising different PAMPs. TLR4-decient mice show an enhanced infection rate of Candida albicans [29]; MMR-decient mice, however, show poor clearing of serum proteins [30] but do not suffer from systemic Candida infections [31], probably owing to LLR redundancy. The C-type lectin BDCA-2 is expressed by plasmacytoid DCs, a subset of DCs that, upon viral infection, produce IFNs, inducing innate antiviral immunity [32]. Crosslinking of BDCA-2 using antibodies induces Ca2 mobilisation, paralleled by tyrosine phosphorylation of cellular proteins. Moreover, IFN secretion induced by various stimuli, such as inuenza virus and bacterial DNA, is inhibited by simultaneous ligation of BDCA-2, indicating that this lectin modulates signalling of TLRs [33] as well. A natural ligand of BDCA-2 has not yet been identied. Mycobacteria can also simultaneously interact with TLRs and C-type lectins. Binding of mycobacterial lipoproteins to TLRs on DCs triggers production of IL-12, essential to initiate immune responses to eliminate intracellular mycobacteria [34]. Interestingly, several groups recently showed that mycobacterium-derived mannosylated lipoarabinomannans binds to DCs via MMR and DC-SIGN and inhibit TLR-mediated IL-12 production [24,3537]. These observations suggest that simultaneous binding of mycobacterium components to MMR, DC-SIGN and TLRs might skew the immune system from a protective Th1 response towards a tolerogenic Th2 response, facilitating immune escape of mycobacteria, demonstrating the critical balance between TLR and LLR signals.

C-type lectin-like and Toll-like receptors are pathogen-recognition receptors

The TLR family is a series of evolutionary highly conserved surface receptors that recognise pathogenassociated molecular patterns (PAMPs) displayed at the cell surface of microorganisms (Box 1). These receptors are referred to as PRRs and recognise bacterial lipopolysaccharides, peptidoglycans, unmethylated CpG motifs of bacterial DNA or double-stranded RNA of viruses. They are related to the Drosophila Toll receptor family [20] and provide an intriguing link between innate and adaptive immunity because of their role in DC activation and maturation [21,22]. In DCs and macrophages, signals through TLRs induce the release of cytokines such as interferons (IFNs) and IL-12 and the upregulation of accessory molecules for efcient stimulation of T cells [23]. Whereas TLRs mainly act to alert DCs, as discussed above overwhelming evidence now shows that C-type LLRs can operate as constituents of the powerful antigen capture and uptake mechanism of macrophages and DCs, as discussed above. Like TLRs, LLRs recognise PAMPs (Box 1); however, unlike TLRs, there is currently no evidence that LLRs can discriminate between self and non-self, suggesting a different mechanism of PAMP recognition and subsequent signalling by LLRs.
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C-type lectin-like receptor specicity as a consequence of differences in ligand glycosylation

Several studies have reported on the importance of LLR ligand glycosylation by transferases and how inammation-induced transferase activity can dramatically alter the homing behaviour of cells. For example, L-selectin mediates rolling of lymphocytes on HEVs in secondary lymphoid organs by interacting with the HEV ligands GlyCAM-1, CD34 and podocalyxin. These ligands must be sialylated, fucosylated and sulphated for optimal
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Dual function of C-type lectin-like receptors in the immune system Cambi and Figdor 543

recognition by L-selectin. In particular, glycosyltransferases are responsible for formation of branched structures of O-glycans on GlyCAM-1 and CD34 [38]. Galactose 6-sulphotransferase shows a wide tissue distribution, but N-acetyl glucosamine (GlcNAc) 6-sulphotransferase is highly restricted to HEVs, thereby contributing to different homing proles. Furthermore, whereas endothelial expression of sLeX or sulpho-sLeX glycans in postcapillary venules is either absent or low, strong expression is observed in inamed tissue, in order to recruit leukocytes [39]. Renkonen et al. [40] have shown that essentially every organ carries its own pattern of sLeX or sulpho-sLeX glycans, suggesting that each organ has its own unique glycan code responsible for organ-selective leukocyte trafc. Their observations also emphasise the major impact of small differences in glycosylation on leukocyte homing. Moreover, leukocytes from P-selectin glycoprotein ligand-1 (PSGL-1)-decient mice show impaired rolling [41]. Similarly, mice decient for core 2 b1-6-N-glucosaminyltransferase (core2/) show dramatically reduced leukocyte rolling, owing to severely impaired binding of P-selectin to PSGL-1 [42]. This not only demonstrates

that PSGL-1 is a major E-/P-selectin ligand but also that proper glycosylation is essential. As well as inammatory cytokines, cytokines such as IL-2 and IL-15, secreted during productive immune responses, induce transferase activity, resulting in altered glycosylation of PSGL-1 [43], reinforcing the concept that the cytokine milieu directly affects the lymphocyte homing properties. Similar to the selectins, ligand binding in the type II C-type lectin group also depends on subtle differences in the arrangements of carbohydrate residues and their branching. For example, MMR, but not DC-SIGN [17], recognises end-standing single mannose moieties, whereas DC-SIGN has higher afnity for more complex mannose residues in specic arrangements [4446]. Thus, even when C-type lectins share a CRD site and bind mannose-containing structures, their counterstructures differ in carbohydrate branching and spacing, creating unique sets of carbohydrate recognition proles on DCs. This is illustrated in Figure 2, where different forms of the LeX blood-group antigen result in binding to completely different C-type LLRs. The cysteine-rich domain of the MMR recognises sulphated oligosaccharides of LeX [6]; DC-SIGN recognises the unsialylated form of LeX [47]; and P- and E-selectin have an afnity for both.

Figure 2

LewisX
HO OH H3C HO HO OH O OH O OH AcHN O O O OH HO HO AcHN HO

Sialyl 6-sulpho-LewisX
HO OH OH HO OOC O O OH H3C OH O OH O OH AcHN O O O OSO3H HO HO AcHN OH HO

Sialyl LewisX
HO OH OH HO OOC O O H3C OH O OH O OH AcHN O O O OH OH

3-sulpho-LewisX
HO OH H3C HO SO4 OH O OH O OH AcHN O O O OH OH

L-selectin DC-SIGN

E-selectin P-selectin

MMR

Current Opinion in Cell Biology

Glycosylation of ligands of C-type LLRs. Minor differences in glycosylation have a major impact on recognition by LLRs. As an example, different glycosylated forms of the blood group antigen Lewis X and the consequences thereof of recognition by LLRs are shown. The micromillieu of the tissues can directly affect protein glycosylation of a cell and thereby dramatically alter ligand recognition. Ac, acetyl. www.current-opinion.com Current Opinion in Cell Biology 2003, 15:539546

544 Cell-to-cell contact and extracellular matrix

Multimerisation of C-type lectin-like receptors

Several C-type LLRs are thought to form multimeric complexes ranging from dimers to tetramers. This is one possible way to increase binding of ligands containing repetitive sugar moieties [48]. Alternatively, conformational changes or clustering of receptors at the cell surface as observed for integrins can also contribute to strong ligand binding. The P-selectin homodimer has unique functional characteristics compared with its monomeric form, and dimerisation occurs in the endoplasmic reticulum and Golgi compartments of endothelial cells (ECs) [49]. Moreover, the CRD of DC-SIGN, when clustered in the tetrameric extracellular domain [48], provides a means of amplifying specicity for multiple repetitive units on host molecules targeted by DC-SIGN [50] and might also explain the interaction of these receptors with the gp120 envelope protein of HIV-1, which contributes to virus infection. We nd DC-SIGN in different levels of organisation (clustering) on DCs, depending on their state of development from monocyte precursors; we have also discovered that LLRs employ multivalency to stabilise ligand binding, similar to other adhesion molecules (Cambi et al. unpublished).

Acknowledgements
We thank Gosse J Adema and Ruurd Torensma for critical reading and discussion. This work was supported by grant SLW 33.302P from the Netherlands Organisation of Scientic Research, Earth and Life Sciences (to A Cambi), and by grant NWO 901-10-092 (to CG Figdor).

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:  of special interest  of outstanding interest 1. Figdor CG, van Kooyk Y, Adema GJ: C-type lectin receptors on dendritic cells and Langerhans cells. Nat Rev Immunol 2002, 2:77-84. Kogelberg H, Feizi T: New structural insights into lectin-type proteins of the immune system. Curr Opin Struct Biol 2001, 11:635-643.

2.

Hayashida K, Kume N, Minami M, Kita T: Lectin-like oxidized LDL receptor-1 (LOX-1) supports adhesion of mononuclear leukocytes and a monocyte-like cell line THP-1 cells under static and ow conditions. FEBS Lett 2002, 511:133-138. These two papers (see also Honjo et al. [2003] [5]) show that LOX-1 can, in addition to its scavenger function, act as a leukocyte adhesion receptor. 4. Kakutani M, Masaki T, Sawamura T: A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1. Proc Natl Acad Sci USA 2000, 97:360-364.

3. 

Conclusions
The recent discovery of a multitude of LLRs expressed by cells of the immune system, and the identication of their function, shows that LLRs in general serve two purposes. First, they mediate cellcell contact, either between leukocytes themselves or to interact with endothelium. Second, surface-bound LLRs function as PRRs on macrophages and DCs (Box 1). In this latter respect, LLRs resemble TLRs, although they are completely different in their signalling function, which remains to be unravelled. The balance between signals from LLRs and TLRs seems critical for the type of immune response generated, resulting either in escape or complete elimination of pathogens. Consequences of differences in glycosylation of LLR ligands have until now been underestimated. They directly affects LLR binding specicity, and have important consequences for the development, survival, migration and reactivity of cells of the immune system [51]. The dazzling complexity of carbohydrate ligands generated by the many glycosyltransferases and glycosidases which add or remove specic carbohydrate moieties, respectively is controlled by the cellular milieu (e.g. cytokines and inammatory mediators), which can dramatically differ not only in the different tissues but also during inammation and leukocyte development. As such, both the adhesive and homing properties of leukocytes and their capacity to bind pathogens vary considerably.
Current Opinion in Cell Biology 2003, 15:539546

Honjo M, Nakamura K, Yamashiro K, Kiryu J, Tanihara H, McEvoy LM, Honda Y, Butcher EC, Masaki T, Sawamura T: Lectinlike oxidized LDL receptor-1 is a cell-adhesion molecule involved in endotoxin-induced inammation. Proc Natl Acad Sci USA 2003, 100:1274-1279. See annotation Hayashida et al. (2002) [3]. 6. Leteux C, Chai W, Loveless RW, Yuen CT, Uhlin-Hansen L, Combarnous Y, Jankovic M, Maric SC, Misulovin Z, Nussenzweig MC et al.: The cysteine-rich domain of the macrophage mannose receptor is a multispecic lectin that recognizes chondroitin sulfates A and B and sulfated oligosaccharides of blood group Lewis(a) and Lewis(x) types in addition to the sulfated N-glycans of lutropin. J Exp Med 2000, 191:1117-1126.

5. 

Irjala H, Johansson EL, Grenman R, Alanen K, Salmi M, Jalkanen S: Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium. J Exp Med 2001, 194:1033-1042. The dual function of macrophage mannose receptor is described. It can act as a scavenger receptor but, under certain conditions, can also function as a cell adhesion receptor. 8. Groger M, Holnthoner W, Maurer D, Lechleitner S, Wolff K, Mayr BB, Lubitz W, Petzelbauer P: Dermal microvascular endothelial cells express the 180-kDa macrophage mannose receptor in situ and in vitro. J Immunol 2000, 165:5428-5434. Geijtenbeek TB, Krooshoop DJ, Bleijs DA, van Vliet SJ, van Duijnhoven GC, Grabovsky V, Alon R, Figdor CG, van Kooyk Y: DCSIGN-ICAM-2 interaction mediates dendritic cell trafcking. Nat Immunol 2000, 1:353-357.

7. 

9.

10. Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR et al.: DC-SIGN, a dendritic cell-specic HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000, 100:587-597. 11. van Kooyk Y, Geijtenbeek TB: A novel adhesion pathway that regulates dendritic cell trafcking and T cell interactions. Immunol Rev 2002, 186:47-56. 12. Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC,  Adema GJ, van Kooyk Y, Figdor CG: Identication of DC-SIGN, a novel dendritic cell-specic ICAM-3 receptor that supports primary immune responses. Cell 2000, 100:575-585. The dual function of DC-SIGN is described, which can act as both an adhesion receptor mediating dendritic cell (DC)T-cell interactions and as an antigen uptake receptor on DCs involved in the pathogenesis of HIV-1. www.current-opinion.com

Dual function of C-type lectin-like receptors in the immune system Cambi and Figdor 545

13. Ariizumi K, Shen GL, Shikano S, Xu S, Ritter R, Kumamoto T, Edelbaum D, Morita A, Bergstresser PR, Takashima A: Identication of a novel, dendritic cell-associated molecule, dectin-1, by subtractive cDNA cloning. J Biol Chem 2000, 275:20157-20167. 14. Ryan EJ, Marshall AJ, Magaletti D, Floyd H, Draves KE, Olson NE, Clark EA: Dendritic cell-associated lectin-1: a novel dendriticcell-associated, C-type lectin-like molecule enhances T cell secretion of IL-4. J Immunol 2002, 169:5638-5648. 15. Mahnke K, Guo M, Lee S, Sepulveda H, Swain SL, Nussenzweig M,  Steinman RM: The dendritic cell receptor for endocytosis, DEC205, can recycle and enhance antigen presentation via major histocompatibility complex class II-positive lysosomal compartments. J Cell Biol 2000, 151:673-684. The authors show that DEC205 acts as an antigen uptake receptor. 16. Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Facchetti F, Gunther G, Johnston I, Lanzavecchia A, Nagasaka T et al.: BDCA-2, a novel plasmacytoid dendritic cell-specic type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Med 2001, 194:1823-1834. 17. Engering A, Geijtenbeek TB, van Vliet SJ, Wijers M, van Liempt E, Demaurex N, Lanzavecchia A, Fransen J, Figdor CG, Piguet V et al.: The dendritic cell-specic adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J Immunol 2002, 168:2118-2126. 18. Schjetne KW, Thompson KM, Aarvak T, Fleckenstein B, Sollid LM, Bogen B: A mouse C(kappa)-specic T cell clone indicates that DC-SIGN is an efcient target for antibody-mediated delivery of T cell epitopes for MHC class II presentation. Int Immunol 2002, 14:1423-1430. 19. Bashirova AA, Geijtenbeek TB, van Duijnhoven GC, van Vliet SJ, Eilering JB, Martin MP, Wu L, Martin TD, Viebig N, Knolle PA et al.: A dendritic cell-specic intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J Exp Med 2001, 193:671-678. 20. Akira S: Mammalian Toll-like receptors. Curr Opin Immunol 2003,  15:238. These papers (see also Medzhitov and Biron (2003) [22]) are excellent overviews of Toll-like receptors. 21. Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002, 296:298-300. 22. Medzhitov R, Biron CA: Innate immunity. Curr Opin Immunol 2003,  15:2-4. See annotation Akira (2003) [20]. 23. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A: Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001, 31:3388-3393. 24. Geijtenbeek TB, Van Vliet SJ, Koppel EA, Sanchez-Hernandez M,  Vandenbroucke-Grauls CM, Appelmelk B, Van Kooyk Y: Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 2003, 197:7-17. The authors show that binding of mycobacterial products through DCSIGN induces IL10 and favours immune escape, antagonising Toll-likereceptor-mediated IL-12 production. 25. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM: Collaborative induction of inammatory responses to dectin-1 and Toll-like receptor 2. J Exp Med 2003, 197:1107-1117. 26. dOstiani CF, Del Sero G, Bacci A, Montagnoli C, Spreca A, Mencacci A, Ricciardi-Castagnoli P, Romani L: Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo. J Exp Med 2000, 191:1661-1674. 27. Fradin C, Poulain D, Jouault T: Beta-1, 2-linked oligomannosides from Candida albicans bind to a 32-kilodalton macrophage membrane protein homologous to the mammalian lectin galectin-3. Infect Immun 2000, 68:4391-4398. www.current-opinion.com

28. Cambi A, Gijzen K, de Vries JM, Torensma R, Joosten B, Adema GJ, Netea MG, Kullberg BJ, Romani L, Figdor CG: The Ctype lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur J Immunol 2003, 33:532-538. 29. Netea MG, Meer JW, Verschueren I, Kullberg BJ: CD40/CD40 ligand interactions in the host defense against disseminated Candida albicans infection: the role of macrophage-derived nitric oxide. Eur J Immunol 2002, 32:1455-1463. 30. Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC: Mannose receptormediated regulation of serum glycoprotein homeostasis. Science 2002, 295:1898-1901. 31. Lee SJ, Zheng NY, Clavijo M, Nussenzweig MC: Normal host defense during systemic candidiasis in mannose receptordecient mice. Infect Immun 2003, 71:437-445. 32. Liu YJ: Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 2001, 106:259-262. 33. Dzionek A, Sohma Y, Nagafune J, Cella M, Colonna M, Cremer S, Facchetti F, Guenther G, Johnston I, Nagasaka T et al.: BDCA-2, a novel plasmacytoid dendritic cell-specic transmembrane protein: Molecular cloning and functional characterization. Keystone Symposium: Dendritic cells, interfaces with immunobiology and medicine. Taos, USA; March 12 2001. 34. Cooper AM, Kipnis A, Turner J, Magram J, Ferrante J, Orme IM: Mice lacking bioactive IL-12 can generate protective, antigen-specic cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J Immunol 2002, 168:1322-1327. 35. Maeda N, Nigou J, Herrmann JL, Jackson M, Amara A, Lagrange PH, Puzo G, Gicquel B, Neyrolles O: The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. J Biol Chem 2003, 278:5513-5516. 36. Maeda N, Nigou J, Herrmann JL, Jackson M, Amara A, Lagrange PH, Puzo G, Gicquel B, Neyrolles O: The cell surface receptor DC-SIGN discriminates between mycobacterium species through selective recognition of the mannose caps on Lipoarabinomannan. J Biol Chem 2003, 278:5513-5516. 37. Tailleux L, Schwartz O, Herrmann JL, Pivert E, Jackson M, Amara A, Legres L, Dreher D, Nicod LP, Gluckman JC et al.: DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J Exp Med 2003, 197:121-127. 38. Bistrup A, Bhakta S, Lee JK, Belov YY, Gunn MD, Zuo FR, Huang CC, Kannagi R, Rosen SD, Hemmerich S: Sulfotransferases of two specicities function in the reconstitution of high endothelial cell ligands for L-selectin. J Cell Biol 1999, 145:899-910. 39. Kannagi R: Regulatory roles of carbohydrate ligands for selectins in the homing of lymphocytes. Curr Opin Struct Biol 2002, 12:599-608. 40. Renkonen J, Tynninen O, Hayry P, Paavonen T, Renkonen R: Glycosylation might provide endothelial zip codes for organspecic leukocyte trafc into inammatory sites. Am J Pathol 2002, 161:543-550. 41. Sperandio M, Thatte A, Foy D, Ellies LG, Marth JD, Ley K:  Severe impairment of leukocyte rolling in venules of core 2 glucosaminyltransferase-decient mice. Blood 2001, 97:3812-3819. These two papers (see also Xia et al. [2002] [42]) describe leukocyte endothelial-cell interactions of cells from transferase-decient mice. They show the importance of proper glycosylation. 42. Xia L, Sperandio M, Yago T, McDaniel JM, Cummings RD, Pearson White S, Ley K, McEver RP: P-selectin glycoprotein ligand-1decient mice have impaired leukocyte tethering to E-selectin under ow. J Clin Invest 2002, 109:939-950. See annotation Sperandio et al. [41]. 43. Carlow DA, Corbel SY, Williams MJ, Ziltener HJ: IL-2, -4, and -15  differentially regulate O-glycan branching and P-selectin ligand formation in activated CD8 T cells. J Immunol 2001, 167:6841-6848. Current Opinion in Cell Biology 2003, 15:539546

546 Cell-to-cell contact and extracellular matrix

The authors show that not only inammatory mediators, but also T-cellderived cytokines, inuence glycosylation patterns and therefore cell adhesion. 44. Mitchell DA, Fadden AJ, Drickamer K: A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organisation and binding to multivalent ligands. J Biol Chem 2001, 276:28939-28945. 45. Feinberg H, Mitchell DA, Drickamer K, Weis WI: Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. Science 2001, 294:2163-2166. 46. Geijtenbeek TB, van Duijnhoven GC, van Vliet SJ, Krieger E, Vriend G, Figdor CG, van Kooyk Y: Identication of different binding sites in the dendritic cell-specic receptor DC-SIGN for intercellular adhesion molecule 3 and HIV-1. J Biol Chem 2002, 277:11314-11320. 47. Appelmelk BJ, Van Die I, Van Vliet SJ, Vandenbroucke-Grauls CM, Geijtenbeek TB, Van Kooyk Y: Cutting edge: carbohydrate proling identies new pathogens that interact with dendritic cell-specic ICAM-3-grabbing nonintegrin on dendritic cells. J Immunol 2003, 170:1635-1639.

48. Mitchell DA, Fadden AJ, Drickamer K: 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 2001, 276:28939-28945. The authors show that C-type lectin-like receptors can form multimers. 49. Barkalow FJ, Barkalow KL, Mayadas TN: Dimerization of Pselectin in platelets and endothelial cells. Blood 2000, 96:3070-3077. 50. Frison N, Taylor ME, Soilleux E, Bousser MT, Mayer R, Monsigny M, Drickamer K, Roche AC: Oligolysine-based oligosaccharide clusters: selective recognition and endocytosis by the mannose receptor and dendritic cell-specic intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin. J Biol Chem 2003, 278:23922-23929. 51. Daniels MA, Hogquist KA, Jameson SC: Sweet n sour: the  impact of differential glycosylation on T cell responses. Nat Immunol 2002, 3:903-910. This is an excellent review because it highlights the complexity of glycosylation and how differential glycosylation can have dramatic effects on the outcome of immune responses.

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