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Dual function of C-type lectin-like receptors in theimmune systemAlessandra 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

andfunctional differences.Theselectins areof major importancein

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 findings 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 Netherlandse-mail: [email protected]

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 domainDC dendritic cellDC-SIGN DC-specific ICAM-3-grabbing non-integrin

EC endothelial cell

GlyCAM-1 glycosylation-dependent cell adhesion molecule 1HEV high endothelial venuleICAM intercellular adhesion molecule

IFN interferon

LLR lectin-like receptorLSEC liver sinusoidal ECMMR macrophage mannose receptor

PAMP pathogen-associated molecular patternPRR pathogen-recognition receptor

sLeX sialyl Lewis XTLR Toll-like receptor

IntroductionCellsof the immunesystem areequipped 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 define leukocytes in more molecular terms

have ledto theidentificationof a series ofgenes that encode

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 structur-

ally related Ca2-dependent carbohydrate-recognition

domains (CRDs). A well-defined subset the selectins

primarilyfunction as cell adhesion receptors that play an

important role in homing of leukocytes. The binding

specificity 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 serummannose-binding protein and pulmonary surfactant pro-

teins, but also the macrophage cell-surface mannose

receptor, is effected by binding of terminal monosacchar-

ide residues characteristic of bacterial and fungal cell

surfaces. The broad selectivity of the monosaccharide-binding 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 expressedby macrophages and

dendritic cells (DCs) andplay a role both as a cell-adhesionreceptor and as a phagocytic pathogen-recognition recep-

tor (PRR). Finally, we shall discuss the importance of

ligand glycosylation with respect to recognition by LLRs.

C-type lectin-like receptors in leukocyte

traffickingThe selectins a family comprising three members (E-,

L- andP-selectin) form theprototypeC-type LLRs that

mediate adhesion and homing to the peripheral tissues.

Both E- andP selectin areexpressed on activatedendothe-

lium 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 identified as

an endothelial scavenger receptor with a C-type LLR

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structure, was shown to support rolling and adhesion of

mononuclear leukocytes [3] and platelets [4] to endothe-

lium. As such, LOX-1 plays an important role in leukocyte

extravasation upon inflammatory stimuli [5].

Similarly, the macrophage mannose receptor (MMR) par-

allels members of the selectinfamily.Through itscysteine-

rich 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 finding that several classes of carbohydrate bind

MMR provides a mechanism for regulating the trafficking

and function of MMR-bearing cells [6]. Recently, MMR

was identified on human lymphatic endothelium to med-

iate 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 entranceand 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 first example of the dual function for an

LLR (Figure 1).

Further evidence for a role of C-type lectins in trafficking

of DCs comes from the observation that intercellular

adhesion molecule 2 (ICAM-2), constitutively expressed

Table 1

Overview of structural and functional relationships of subfamilies of C-type lectin-like receptors.

Group and

molecular structureC-type lectin Localisation Ligand

specificity

Function Cytoplasmic tail

motif (single letter

amino acid code)

VI. MMR family MMR

DEC-205

Endo180

DCs, LC, Mo, Mf, LE

DMECs

DCs, LC, tEC,

fibroblasts

Mannose,

fucose, sLeX

?

Collagen

Antigen uptake,

cell adhesion

Antigen uptake

ECM degradation

FENTLY

FSSVRY EDE

FEGARY

V. NK receptors

-ss-

b-GR (dectin-1)

CLEC-1

CLEC-2

LOX-1

DCs, LC

DCs

DCs

vEC, Mf

b-Glucan

?

?

ox-LDL, AGE, aPL

Antigen uptake, cell adhesion

?

?

Phagocytosis

YTQL DED

YSST DDD

YITL

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

Mannan, LeX,

fucose

Mannan

?

?

?

?

Antigen uptake,

cell adhesion

Antigen uptake

?

Birbeck granules format

T cell co-stimulation

Antigen uptake?

YKSL LL EEE

LL EED

ITYAEV

EEE

IV. Selectins L-selectin

P-selectin

E-selectin

Leukocytes

Platelets, endothelium

Activated endothelium

s6SLeX

sLeX, s6SLeX

sLeX, s6SLeX

Leukocytes tethering:

homing and inflammation

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.

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 cellcellcontact 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

540 Cell-to-cell contact and extracellular matrix

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by endothelium supports tethering and rolling of cells

expressing DC-specific ICAM-3-grabbing non-integrin(DC-SIGN) [9]. DC-SIGNICAM-2 interactions regu-

late chemokine-induced transmigration of DCs across

both resting and activated endothelium in vitro, indicat-

ing that DC-SIGN next to its capacity to bind patho-

gens [10] such as HIV-1 is central to this unusual

trafficking capacity of DCs [9,11].

Antigen-presenting-cellT-cell interactionsProliferation 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

early, antigen-nonspecific contact between DCs and T

cells, enabling T-cell receptor engagement by stabilisa-tion 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 proteinsof 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 undefined cellular ligands or carbohydrates on T

cells, thereby delivering T cell co-stimulatory signals.

Antigen uptake by C-type lectin-likereceptorsSeveral C-type LLRs also participate in pathogen recog-

nition and uptake. As well as the classical MMR, which is

known to act as an endocytic receptor, DEC-205 [15],

Figure 1

Current Opinion in Cell Biology

T cell

Cell adhesion, homing,co-stimulation

DCTLR-7TLR-9

TLR-2

TLR-4

MMR

DEC-205

DC-SIGN

ICAM-3?

LOX

-1

MMR

P-selectin

E-sele

ctin

CD

-34

ICAM

-2

Endothelium

L-sele

ctin

PSGL-

1

MMR

DC

-SIGN

Viruses

HIV-1

EbolaCMVDengueHepatitis C

Bacteria

MycobacteriumHelicobacter

Fungi

Candida

Parasites

LeishmaniaSchistosoma

Pathogen recognition, endocytosis

L-selectinPSGL-1

DC-SIGNDCAL-1

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 withintracellularly expressed TLRs (TLR-7, -9). Other LLRs (selectins, DCAL-1, DC-SIGN, MMR) have an important function in mediating contact (DC T-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.

Dual function of C-type lectin-like receptors in the immune system Cambi and Figdor 541



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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 DC-

SIGN deliver antigens to late endosomes or lysosomes,

where they are degraded. As well as the tyrosine-basedcoated 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 DEC-

205, BDCA-2, CLEC-1 and DC-SIGN contain an addi-

tional 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 homolo-

gue of DC-SIGN designated L-SIGN has the same

ligand-binding specificities 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 potentiallyantigenic proteins from the circulation, in a manner

similar to DCs in lymphoid organs.

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

pathogen-recognition receptorsThe TLR family is a series of evolutionary highly con-

served surface receptors that recognise pathogen-

associated molecular patterns (PAMPs) displayed at the

cell surface of microorganisms (Box1). These receptors are

referred to as PRRs and recognise bacterial lipopolysac-

charides, peptidoglycans, unmethylated CpG motifs of

bacterial DNA or double-stranded RNA of viruses. Theyarerelated to theDrosophila Toll receptorfamily [20] and

provide an intriguing link between innate and adaptive

immunity because of their role in DC activation and matu-

ration [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 mole-cules for efficient 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.

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, med-

iates attachment and uptake of fungi, exploiting itsimmunoreceptor 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. TLR-

4-deficient mice show an enhanced infection rate of

Candida albicans [29]; MMR-deficient mice, however,

show poor clearing of serum proteins [30] but do not

suffer from systemic Candida infections [31], probablyowing 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]. Cross-

linking of BDCA-2 using antibodies induces Ca2 mobi-

lisation, paralleled by tyrosine phosphorylation of cellular

proteins. Moreover, IFN secretion induced by various

stimuli, such as influenza 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 identified.

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 intracellularmycobacteria [34].

Interestingly, several groups recently showed that myco-

bacterium-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 myco-bacterium 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 cri-

tical balance between TLR and LLR signals.

C-type lectin-like receptor specificity as aconsequence of differences in ligandglycosylationSeveral studies have reported on the importance of LLR

ligand glycosylation by transferases and how inflamma-

tion-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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recognition by L-selectin. In particular, glycosyltrans-

ferases are responsible for formation of branched struc-

tures of O-glycans on GlyCAM-1 and CD34 [38].

Galactose 6-sulphotransferase shows a wide tissue dis-

tribution, but N-acetyl glucosamine (GlcNAc) 6-sulpho-transferase is highly restricted to HEVs, thereby

contributing to different homing profiles. Furthermore,

whereas endothelial expression of sLeX or sulpho-sLeX

glycans in postcapillary venules is either absent or low,

strong expression is observed in inflamed 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 traffic. Their observations alsoemphasise the major impact of small differences in gly-

cosylation on leukocyte homing.

Moreover, leukocytes from P-selectin glycoprotein

ligand-1 (PSGL-1)-deficient mice show impaired rolling

[41]. Similarly, mice deficient for core 2 b1-6-N-gluco-

saminyltransferase (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 inflammatory

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 milieudirectly 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 affinity for more complex

mannose residues in specific arrangements [4446]. Thus,

even when C-type lectins share a CRD site and bindmannose-containing structures, their counterstructures

differ in carbohydrate branching and spacing, creating

unique sets of carbohydrate recognition profiles on DCs.

This is illustrated in Figure 2, where different forms of

the LeX blood-group antigen result in binding to com-

pletely 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 affinity for both.

Figure 2

Current Opinion in Cell Biology

L-selectin E-selectinP-selectin MMRDC-SIGN

LewisX Sialyl 6-sulpho-LewisX Sialyl LewisX 3-sulpho-LewisX

O

OHHO

H3C

OH

O O

AcHNOH

OHOO

OH

OH

HO

HO

O

OHHO

H3C

OH

O O

AcHNOH

OSO3HOO

OH

OH

O

HO

O

OOC

OHAcHN

HO

HO

HO

O

OHHO

H3C

OH

O O

AcHNOH

OHOO

OH

OH

O

HO

O

OOC

OHAcHN

HO

HO

HO

O

OHHO

H3C

OH

O O

AcHNOH

OHOO

OH

OH

SO4

HO

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.




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Multimerisation of C-type lectin-likereceptorsSeveral 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, conforma-tional changes or clustering of receptors at the cell sur-

face 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 endo-

plasmic reticulum and Golgi compartments of endothe-

lial cells (ECs) [49]. Moreover, the CRD of DC-SIGN,

when clustered in the tetrameric extracellular domain

[48], provides a means of amplifying specificity for

multiple repetitive units on host molecules targetedby 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 find

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 bind-

ing, similar to other adhesion molecules (Cambi et al.

unpublished).

ConclusionsThe recent discovery of a multitude of LLRs expressed

by cells of the immune system, and the identification of

their function, shows that LLRs in general serve two

purposes. First, they mediate cellcell contact, either

between leukocytes themselves or to interact withendothelium. Second, surface-bound LLRs function as

PRRs on macrophages and DCs (Box 1). In this latter

respect, LLRs resemble TLRs, although they are com-

pletely 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 specificity, 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 glyco-

sidases which add or remove specific carbohydratemoieties, respectively is controlled by the cellular

milieu (e.g. cytokines and inflammatory mediators),

which can dramatically differ not only in the different

tissues but also during inflammation and leukocyte

development. As such, both the adhesive and homing

properties of leukocytes and their capacity to bind

pathogens vary considerably.

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

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

of special interestof outstanding interest

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3.

Hayashida K, Kume N, Minami M, Kita T: Lectin-like oxidized LDLreceptor-1 (LOX-1) supports adhesion of mononuclearleukocytes and a monocyte-like cell line THP-1 cells understatic and flow conditions. FEBS Lett 2002, 511:133-138.

These two papers (see also Honjo et al. [2003] [5]) show that LOX-1can, in addition to its scavenger function, act as a leukocyte adhesionreceptor.

4. Kakutani M, Masaki T, Sawamura T: A platelet-endotheliuminteraction mediated by lectin-like oxidized low-densitylipoprotein receptor-1. Proc Natl Acad SciUSA 2000, 97:360-364.

5.

Honjo M, Nakamura K, Yamashiro K, Kiryu J, Tanihara H,McEvoyLM, Honda Y, Butcher EC,Masaki T, Sawamura T: Lectin-like oxidized LDL receptor-1 is a cell-adhesion moleculeinvolved in endotoxin-induced inflammation. Proc Natl Acad SciUSA 2003, 100:1274-1279.

See annotation Hayashida et al. (2002) [3].

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The dual function of macrophage mannose receptor is described. It canact as a scavenger receptor but, under certain conditions, can alsofunction as a cell adhesion receptor.

8. Groger M, Holnthoner W, Maurer D, Lechleitner S, Wolff K,Mayr BB, Lubitz W, Petzelbauer P: Dermal microvascularendothelial cells express the 180-kDa macrophage mannosereceptor in situ and in vitro. J Immunol 2000, 165:5428-5434.

9. Geijtenbeek TB, Krooshoop DJ, Bleijs DA, van Vliet SJ, vanDuijnhoven GC,Grabovsky V, Alon R, FigdorCG, vanKooyk Y: DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking.Nat Immunol 2000, 1:353-357.

10. Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ,van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, Kewal-Ramani VN, Littman DR et al.: DC-SIGN, a dendritic cell-specificHIV-1-binding protein that enhances trans-infection of T cells.Cell 2000, 100:587-597.

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Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC,Adema GJ, van Kooyk Y, Figdor CG: Identification of DC-SIGN, anovel dendritic cell-specific ICAM-3 receptor that supportsprimary immune responses. Cell 2000, 100:575-585.

The dual function of DC-SIGN is described, which can act as both anadhesion receptor mediating dendritic cell (DC)T-cell interactions and asan antigen uptakereceptor on DCsinvolvedin thepathogenesis of HIV-1.




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13. Ariizumi K, Shen GL, Shikano S, Xu S, Ritter R, Kumamoto T,Edelbaum D, Morita A, Bergstresser PR, Takashima A:Identification 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 dendritic-

cell-associated, C-type lectin-like molecule enhances T cellsecretion of IL-4. J Immunol 2002, 169:5638-5648.

15.

MahnkeK, Guo M, LeeS, Sepulveda H, Swain SL, Nussenzweig M,Steinman RM: The dendritic cell receptor for endocytosis, DEC-205, can recycle and enhance antigen presentation via majorhistocompatibility complex class II-positive lysosomalcompartments. 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, JohnstonI, Lanzavecchia A, Nagasaka T etal.: BDCA-2,a novel plasmacytoid dendritic cell-specific type II C-typelectin, mediates antigen capture and is a potent inhibitorof 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, LanzavecchiaA, Fransen J, FigdorCG, PiguetV etal.:The dendritic cell-specific adhesion receptor DC-SIGN

internalizes antigen for presentation to T cells. J Immunol2002,168:2118-2126.

18. Schjetne KW, Thompson KM, Aarvak T, Fleckenstein B, Sollid LM,Bogen B: A mouse C(kappa)-specific T cell clone indicates thatDC-SIGN isan efficient target forantibody-mediateddelivery ofT cell epitopes for MHC class II presentation. Int Immunol2002,14:1423-1430.

19. Bashirova AA, Geijtenbeek TB, van Duijnhoven GC, van Vliet SJ,Eilering JB, Martin MP, Wu L, Martin TD, Viebig N, Knolle PAet al.:A dendri tic cell- specific intercellular adhesion molecule3-grabbing nonintegrin (DC-SIGN)-related protein ishighly expressed on human liver sinusoidal endothelialcells and promotes HIV-1 infection. J Exp Med 2001,193:671-678.

20.

Akira S: Mammalian Toll-like receptors. Curr Opin Immunol2003,15:238.

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 selfand nonself by the innate immune system. Science 2002,296:298-300.

22.

MedzhitovR, Biron CA: Innate immunity. Curr Opin Immunol2003,15:2-4.

See annotation Akira (2003) [20].

23. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A:Specialization and complementarity in microbial moleculerecognition by human myeloid and plasmacytoid dendriticcells. 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 cellfunction. J Exp Med 2003, 197:7-17.

The authors show that binding of mycobacterial products through DC-

SIGN induces IL10 and favours immune escape, antagonising Toll-like-receptor-mediated IL-12 production.

25. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM:Collaborative induction of inflammatory responses to dectin-1and 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 cellsdiscriminate between yeasts and hyphae of the fungusCandida albicans. Implications for initiation of T helpercell immunity in vitro and in vivo. J Exp Med 2000,191:1661-1674.

27. Fradin C, Poulain D, Jouault T: Beta-1, 2-linked oligomannosidesfrom Candida albicans bind to a 32-kilodalton macrophagemembrane protein homologous to the mammalian lectingalectin-3. Infect Immun 2000, 68:4391-4398.

28. Cambi A, Gijzen K, de Vries JM, Torensma R, Joosten B,Adema GJ, Net ea MG, Kullberg BJ, Rom ani L, Figdor CG: The C-type lectinDC-SIGN(CD209) is an antigen-uptake receptor forCandida albicans on dendritic cells. Eur J Immunol 2003,33:532-538.

29. Netea MG, Meer JW, Verschueren I, Kullberg BJ: CD40/CD40ligand interactions in the host defense against disseminated

Candida albicans infection: the role of macrophage-derivednitric 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 receptor-mediated regulation of serum glycoprotein homeostasis.Science 2002, 295:1898-1901.

31. Lee SJ, Zheng NY, Clavijo M, Nussenzweig MC: Normal hostdefense during systemic candidiasis in mannose receptor-deficient mice. Infect Immun 2003, 71:437-445.

32. Liu YJ: Dendritic cell subsets and lineages, and their functionsin 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, anovel plasmacytoid dendritic cell-specific transmembraneprotein: 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-specific cellular responses to mycobacterialinfection only if the IL-12 p40 subunit is present . J Immunol2002, 168:1322-1327.

35. Maeda N, Nigou J, Herrmann JL, Jackson M, Amara A,Lagrange PH, Puzo G, Gicquel B, Neyrolles O: The cell surfacereceptor DC-SIGN discriminates between Mycobacteriumspecies through selective recognition of the mannose caps onlipoarabinomannan. 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 surfacereceptor DC-SIGN discriminates between mycobacteriumspecies through selective recognition of the mannose caps onLipoarabinomannan. J Biol Chem 2003, 278:5513-5516.

37. Tailleux L, Schwartz O, HerrmannJL, PivertE, Jackson M, Amara A,Legres L, Dreher D, Nicod LP, Gluckman JC et al.: DC-SIGN is themajor Mycobacterium tuberculosis receptor on humandendritic 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 specificities function in thereconstitution of high endothelial cell ligands for L-selectin.J Cell Biol 1999, 145:899-910.

39. Kannagi R: Regulatory roles of carbohydrate ligands forselectins in the homing of lymphocytes. Curr Opin Struct Biol2002, 12:599-608.

40. Renkonen J, Tynninen O, Hayry P, Paavonen T, Renkonen R:Glycosylation might provide endothelial zip codes for organ-specific leukocyte traffic into inflammatory sites. Am J Pathol2002, 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 2glucosaminyltransferase-deficient mice. Blood 2001,97:3812-3819.

These two papers (see also Xia et al. [2002] [42]) describe leukocyteendothelial-cellinteractions of cells from transferase-deficient mice. Theyshow the importance of proper glycosylation.

42.

XiaL, SperandioM, Yago T, McDaniel JM,CummingsRD, Pearson-White S, Ley K, McEver RP: P-selectin glycoprotein ligand-1-deficient mice have impaired leukocyte tethering to E-selectinunder flow. 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 -15differentially regulate O-glycan branching and P-selectinligand formation in activated CD8 T cells. J Immunol 2001,167:6841-6848.




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The authors show that not only inflammatory mediators, but also T-cell-derived cytokines, influence glycosylation patterns and therefore celladhesion.

44. Mitchell DA, Fadden AJ, Drickamer K: A novel mechanism ofcarbohydrate recognition by the C-type lectins DC-SIGN andDC-SIGNR. Subunit organisation and binding to multivalentligands. J Biol Chem 2001, 276:28939-28945.

45. Feinberg H, Mitchell DA, Drickamer K, Weis WI: Structural basisfor selective recognition of oligosaccharides by DC-SIGN andDC-SIGNR. Science 2001, 294:2163-2166.

46. Geijtenbeek TB, van Duijnhoven GC, van Vliet SJ, Krieger E,Vriend G, Figdor CG, van Kooyk Y: Identification of differentbinding sites in thedendritic cell-specific receptor DC-SIGN forintercellular 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: carbohydrateprofiling identifies new pathogens that interact with dendriticcell-specific ICAM-3-grabbing nonintegrin on dendritic cells.J Immunol 2003, 170:1635-1639.

48.

Mitchell DA, Fadden AJ, Drickamer K: A novel mechanism ofcarbohydrate recognition by the C-type lectins DC-SIGN andDC-SIGNR. Subunit organization and binding to multivalentligands. 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 P-selectin in platelets and endothelial cells. Blood 2000,

96:3070-3077.

50. Frison N, Taylor ME,SoilleuxE, Bousser MT,MayerR, Monsigny M,Drickamer K, Roche AC: Oligolysine-based oligosaccharideclusters: selective recognition and endocytosis by themannose receptor and dendritic cell-specific intercellularadhesion molecule 3 (ICAM-3)-grabbing nonintegrin. J BiolChem 2003, 278:23922-23929.

51.

Daniels MA, Hogquist KA, Jameson SC: Sweet n sour: theimpact of differential glycosylation on T cell responses .Nat Immunol 2002, 3:903-910.

This is an excellent review because it highlights the complexity ofglycosylation and how differentialglycosylationcan havedramatic effectson the outcome of immune responses.



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