REF 29 DC SIGN ESCAPE MECHANISM Entrada Mol Adhesion PDF

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DC-SIGN: ESCAPE MECHANISM

FOR PATHOGENS
Yvette van Kooyk and Teunis B. H. Geijtenbeek
Dendritic cells (DCs) are crucial in the defence against pathogens. Invading pathogens are
recognized by Toll-like receptors (TLRs) and receptors such as C-type lectins expressed on the
surface of DCs. However, it is becoming evident that some pathogens, including viruses, such as
HIV-1, and non-viral pathogens, such as Mycobacterium tuberculosis, subvert DC functions to
escape immune surveillance by targeting the C-type lectin DC-SIGN (DC-specific intercellular
adhesion molecule-grabbing nonintegrin). Notably, these pathogens misuse DC-SIGN by distinct
mechanisms that either circumvent antigen processing or alter TLR-mediated signalling, skewing
T-cell responses. This implies that adaptation of pathogens to target DC-SIGN might support
pathogen survival.
Department of Molecular
Cell Biology and
Immunology Vrije
Universiteit Medical Center
Amsterdam, v.d.
Boechorststraat 7, 1081 BT
Amsterdam,
The Netherlands.
Correspondence to Y. v. K.
e-mail: Y.vankooyk@vumc.nl
doi:10.1038/nri1182
Dendritic cells (DCs) are instrumental in the development of pathogen-specific immune responses.
Immature DCs, localized in peripheral mucosal tissues
throughout the body, are the immunological sensors
that monitor for pathogens, and relay their information
to lymphocytes to induce an effective immune response
to eliminate the pathogen1. Once a DC has sensed and
captured a pathogen it undergoes considerable changes,
resulting in DC maturation that occurs during the
process of migration from peripheral tissues to draining
lymph nodes. Meanwhile, DCs process pathogens and
express co-stimulatory molecules to set the stage for
effective T-cell stimulation2. Recognition of pathogens
by DCs is one of the most crucial steps in the induction
of protective immunity.
DCs express a repertoire of pathogen-recognition
receptors (PRRs), including Toll-like receptors (TLRs)
and C-type lectins that can recognize molecular
patterns expressed by pathogens. Depending on the
pathogens that are recognized by DCs, naive T cells differentiate into T helper 1 (TH1) cells, which secrete
interferon- (IFN-), or into TH2 cells, which produce
interleukin-4 (IL-4)3. The DC response is modulated
depending on the type or form of a microorganism
that is recognized by different TLRs and C-type lectins.
For example, the yeast form of Candida albicans
induces TH1-cell responses through the induction of
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IL-12 production by DCs, whereas the hyphal form

inhibits IL-12 production and stimulates IL-4 production by DCs4.Although tightly regulated, the induction of
TH1- or TH2-cell responses is susceptible to manipulation
by pathogens.
Here, we review how DCs handle pathogens, and
how pathogens, in their quest for survival, have evolved
several ways to escape immunity by subverting DC
function, especially through the manipulation of PRRs
such as the C-type lectin DC-SIGN (DC-specific intercellular adhesion molecule-grabbing nonintegrin).
Specific receptors for pathogen recognition
Immature DCs screen for pathogen entry using conserved PRRs, which recognize characteristic molecular
patterns in microbial cell-wall components, such as carbohydrate structures, or lipids or nucleic acids5. These
receptors include the TLRs6,7 and the C-type lectins8
(FIG. 1). Each TLR recognizes specific pathogenic components, such as lipoprotein, lipopolysaccharide (LPS)
or bacterial DNA9,10. TLRs relay information about the
interacting pathogen to DCs through intracellularsignalling cascades, thereby eliciting appropriate cellular processes that lead to DC maturation and the
induction of inflammatory cytokines5,6. By contrast,
C-type lectins recognize specific carbohydrate structures
that are present on cell-wall components of pathogens,
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2003 Nature Publishing Group
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Carbohydrate structure on
pathogen or self protein
Pathogen or pathogenic
component
C-type
lectin
TLR
Internalization and
antigen presentation
TCR
T cell
MHC class II
Lysosome
NF-B
Co-stimulatory and
adhesion molecules
Cytokine production
DC
Figure 1 | C-type lectins and Toll-like receptors: pathogen receptors on dendritic cells.
For the recognition of microorganisms, immature dendritic cells (DCs) express Toll-like receptors
(TLRs) and C-type lectins that bind specific pathogen components and carbohydrate structures,
respectively. After recognition by TLRs a signal-transduction cascade is induced, which through
the activation of nuclear factor-B (NF-B) results in the upregulation of expression of costimulatory molecules and adhesion molecules, and the production of cytokines, leading to DC
maturation. The recognition of pathogens by C-type lectins leads to internalization of pathogens
and intracellular processing for presentation by MHC class I and II molecules to T cells. TCR,
T-cell receptor.
and internalize pathogens for degradation in lysosomal compartments to enhance antigen processing and
presentation by DCs11,12 (FIG. 1). C-type lectins also recognize carbohydrate structures on self glycoproteins
to allow tolerance to self antigens and to mediate cellular processes, such as cell signalling, cell adhesion
and migration11.
Expression of TLRs and C-type lectins. Depending on
their tissue localization and differentiation state, DCs are
specialized to respond to specific microorganisms by
expressing distinct sets of TLRs and C-type lectins. Many
different C-type lectins expressed by DCs have been
described11, such as the mannose receptor (CD206)13,
DEC205 (CD205)14, DC-SIGN (CD209)15, blood DC
antigen 2 (BDCA2)16, dectin-1 (REF. 17), DC immunoreceptor (DCIR)18, DC-associated lectin 1 (DCAL1)19,
C-type lectin receptor 1 (CLEC1)20, Langerhans-cellspecific C-type lectin (Langerin, CD207)21 and DCasialoglycoprotein receptor (DC-ASGPR)22/macrophage
galactose N-acetyl-galactosamine specific lectin 1
(MGL1)23 (TABLE 1). Many of these C-type lectins have
been shown to function as antigen receptors11. Monocytederived DCs and interstitial DCs express the highest
diversity of C-type lectins. By contrast, only a few C-type
lectins have been identified on DCs from the blood and
Langerhans cells. Langerhans cells specifically express
Langerin, whereas plasmacytoid DCs express BDCA2
and dectin-1. In particular, C-type lectins are expressed
by immature DCs in the skin or mucosal tissues.
The C-type lectin DC-SIGN, which is involved in the
capture of different pathogens, is expressed by dermal
DCs, as well as in the mucosal tissues by interstitial DCs
in the lungs, intestine, rectum, cervix and placenta, as
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| SEPTEMBER 2003 | VOLUME 3
well as in lymph nodes15,24. After DC maturation, the

expression of C-type lectins is often reduced. DC-SIGN
is frequently co-expressed with the mannose receptor.
Expression of DC-SIGN is mainly induced by IL-4,
whereas the mannose receptor is mainly induced by
granulocytemacrophage colony-stimulating factor
(GM-CSF)25, indicating a preferential TH2-cell-driven
expression of DC-SIGN.
Reflecting the large variety of C-type lectin expression by monocyte-derived DCs and interstitial DCs, a
large diversity of TLRs is also expressed by these DC
subsets26. Myeloid DCs express TLR2, TLR4 and TLR6,
whereas plasmacytoid DCs express TLR7 and TLR9
(REFS 27,28). The finding that distinct DC subsets express
different sets of TLRs and C-type lectins indicates that
different subsets of DCs might be specialized to recognize distinct classes of pathogens and to allow the generation of alternative TH1- or TH2-cell responses. Although
the subset specificity of most C-type lectins is well characterized for DCs cultured in vitro, the co-expression of
C-type lectins and TLRs in tissues is still an unexplored
field of research.
Characteristics of C-type lectins. Most C-type lectins
expressed by DCs are type II transmembrane proteins
(BOX 1) with the exception of the mannose receptor and
DEC205, which are both type I transmembrane proteins11.All type II C-type lectins contain one carbohydrate
recognition domain (CRD)8, whereas the mannose receptor and DEC205 contain eight and ten CRDs, respectively.
Ligand binding by C-type lectins is calcium dependent
and two Ca2+-binding sites are present on a loop that protrudes from the protein surface. Mutation of these sites
leads to the loss of ligand binding29. The valine residue in
the CRD of DC-SIGN has been shown to be involved
in the recognition of some ligands, but not all, indicating
that ligands have different, but overlapping, binding sites.
The presence of a Glu-Pro-Asn site in the CRD predicts
specificity for mannose-containing carbohydrate structures, whereas the presence of a Gln-Pro-Asp site (present
in DC-ASGPR/MGL1) determines specificity for galactose-containing carbohydrate structures3032. Despite the
fact that DC-SIGN, mannose receptor, Langerin and
BDCA2 recognize distinct mannose structures that differ
in branching and spacing, they all contain the GluPro-Asn site in their CRD region13,15,22,3337. The CRD of
DC-SIGN is separated from the transmembrane
region by a neck domain. The neck domain of DCSIGN consists of seven to eight repetitive sequences
that are thought to affect the formation of oligomers
and subsequently influence carbohydrate specificity35
(BOX 1). Oligomerization of lectin domains has been
shown to alter the affinity and specificity of carbohydrate recognition38. Notably, the mannose receptor and
MGL1 form trimers, whereas DC-SIGN has been
shown to form tetramers35, which could explain their
distinct carbohydrate-binding specificities39.
Internalization by C-type lectins. The main function of
C-type lectins expressed by DCs is to interact with conserved molecular patterns that are shared by a large group
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of microorganisms, and internalize these pathogens for
processing and antigen presentation, thereby initiating
immune responses against a diversity of microorganisms40,41. To internalize pathogens most of these C-type
lectins contain putative internalization motifs, such as
the di-leucine (Leu-Leu) motif and the tri-acidic (GluGlu-Glu) clusters42 (BOX 1). Most of the C-type lectins
can function as endocytic receptors as shown by their
capacity to internalize lectin-specific antibodies11, as
internalization of mouse IgG has been shown to lead to
antigen presentation to mouse immunoglobulin-specific
T cells12. Most C-type lectins that have a tri-acidic cluster
(DEC205, DC-SIGN, BDCA2, dectin-1 and CLEC1) target internalized antigens to lysosomes and MHC class IIpositive late endosomes14,43,44. By contrast, other C-type
lectins, such as the mannose receptor, quickly recycle
though early endosomes, to ensure large amounts of
antigen uptake. Although most C-type lectins are endocytic receptors, it is unknown whether they can route
different antigens to different intracellular compartments. Also, the cargo that is carried by the C-type
lectins might determine the intracellular compartment
to which C-type lectins route42,45. So far, there is little
evidence for antigen presentation in vivo. However, antigens targeted to DEC205 and the mannose receptor
have been shown to be processed by DCs for presentation by both MHC class I and II molecules, leading to
enhanced and efficient antigen presentation that allows
low concentrations of antigen to be presented efficiently
to T cells4648 (FIG. 1).
Self and non-self recognition by C-type lectins
C-type lectins are not only involved in the recognition

of pathogens, but also might contribute to the capture
and presentation of glycosylated self antigens. For
example, the mannose receptor recognizes lysosome
hydrolases, certain collagen-like peptides in serum49 and
thyroglobulin a well-known autoantigen 36
Table 1 | Expression of C-type lectins and Toll-like receptors by DCs

Dendritic-cell subsets
C-type lectins
Toll-like receptors
Plasmacytoid DCs
BDCA2
Dectin-1
TLR7
TLR9
Myeloid DCs
DC-SIGN*
DEC205
TLR1
TLR2
TLR3
TLR4
Blood
Tissues
Langerhans cells
Langerin
Monocyte-derived DCs
MGL1
DC-SIGN
Mannose receptor
CLEC1
DCIR
DEC205
DCAL
TLR1
TLR2
TLR3
TLR4
TLR5
*Subset of CD14+ blood dendritic cells (DCs) that co-express DC-SIGN. BDCA2, blood DC antigen
2; CLEC1, C-type lectin receptor 1; DCAL, DC-associated lectin 1; DCIR, DC immunoreceptor; DCSIGN, DC-specific intercellular adhesion molecule-grabbing nonintegrin; Langerin, Langerhans-cellspecific C-type lectin; MGL1, macrophage galactose N-acetyl-galactosamine specific lectin 1; TLR,
Toll-like receptor.
and might have a role in autoimmunity50. DC-SIGN

recognizes the self glycoproteins intercellular adhesion
molecule 2 (ICAM2) and ICAM3, and functions as a
cell-adhesion receptor that regulates DC migration51
and DCT-cell interactions15, respectively. The importance of DC-SIGNICAM3 interactions in the initial
DCT-cell contact is emphasized by the potency of
DC-SIGN-specific antibodies to inhibit DCT-cell
clustering and DC-induced proliferation of resting
T cells15. The transient interaction of DC-SIGN with
ICAM3 allows screening of the peptideMHC complexes by T cells15 and stabilizes the intimate DCT-cell
membrane contact, enabling efficient engagement of
the T-cell receptor (TCR)15,53.
DC-SIGN also functions as a rolling receptor on
DCs to mediate transendothelial migration of DC precursors from blood to tissues by binding endothelial
ICAM2 (REF. 51). In this way, DC-SIGN functions similarly to selectins, which are also members of the C-type
lectin family, functioning as cell-adhesion receptors that
recognize specific carbohydrate structures, such as sialyl-Lewis X (Lex), present on endothelial cells thereby
mediating leukocyte rolling and migration55,56. Both
ICAM2 and ICAM3 are heavily glycosylated glycoproteins that potentially contain high mannose-type
oligosaccharides57,58. Enzymatic removal of the N-linked
carbohydrates from ICAM2 and ICAM3 abrogates
binding to DC-SIGN29. Interestingly, cell-specific glycosylation of ICAM2 and ICAM3 determines whether
the specific carbohydrate structures are recognized by
DC-SIGN. This indicates that cell- and tissue-specific
glycosylation is a strong regulatory element in DC-SIGNmediated cellcell interactions. Cell- and tissue-specific
glycosylation of a glycoprotein (post-translational modification) is mediated by the expression of different glycosyltransferases and glycosidases, which add or remove
specific carbohydrate residues. The expression of these
enzymes changes during the differentiation and activation of lymphocytes. Because carbohydrates interact
specifically with lectins, altered glycosylation of a glycoprotein can modify its recognition by C-type lectins and
subsequently influence cellcell interactions59. Tissueand cell-specific homing and migration by selectins have
been shown to be driven by the expression of a selected
set of fucosyltransferases, resulting in the expression
of specific carbohydrate structures55. Understanding
the carbohydrate specificity of DC-SIGN and other
DC-expressed C-type lectins is a recent topic of interest in the field of glycobiology and immunology60 (see
further information for a relevant website).
Recognition of carbohydrates by C-type lectins
Understanding the exact specificity of C-type lectins for

carbohydrate structures leads to an improved knowledge
about the recognition of self and non-self antigen by
these receptors. The mannose receptor, DC-SIGN and
Langerin have been shown to recognize mannosecontaining carbohydrates, but with a different specificity,
as dictated by branching of the mannose structures.
Whereas the mannose receptor recognizes end-standing
single mannose branched structures or di-mannose
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clusters, DC-SIGN recognizes both internal mannose
branched structures with a minimum of three mannoses
(high mannose) and end-standing di-mannoses15,34,39.
Furthermore, the recognition of specific carbohydrate
structures by DC-SIGN seems to depend on the spacing
of the carbohydrate structures on a glycoprotein35.
Screening panels of synthetic glycoconjugates that
contain mannose, galactose or fucose residues and their
multimeric derivatives were used to determine further
the specificity of C-type lectins6062. This indicated that
DC-SIGN has a higher specificity for fucose-containing
Box 1 | C-type lectins: structure,specificity and function

C-type lectins are transmembrane proteins that act as cell-adhesion receptors, are
involved in the regulation of signalling pathways and recognize specific carbohydrate
structures that are present on self antigens and pathogens.
Here, DC-SIGN (dendritic cell (DC)-specific intercellular adhesion molecule-grabbing
nonintegrin) a prototype type II transmembrane C-type lectin is depicted. As
shown, DC-SIGN consists of a carbohydrate recognition domain (CRD) that binds
carbohydrate residues such as Lewis-x and high mannose or mannose-cap (as present in
ManLAM the mannose-capped cell-wall component of Mycobacteria tuberculosis
lipoarabinomannan). Carbohydrate ligands interact directly with Ca2+ through hydroxyl
groups and hydrogen bonds with amino-acid side chains (Glu-Asn) that also act as Ca2+
coordination ligands.
The CRD of DC-SIGN is a globular structure consisting of 12 -strands, two -helices
and three disulphide bridges. A loop protrudes from the protein surface and forms part
of two Ca2+-binding sites. One of these Ca2+ sites is essential for the conformation of the
CRD, whereas the other Ca2+ site is essential for direct coordination of the carbohydrate
structures. Four amino acids (Glu347, Asn349, Glu354 and Asn365) interact with Ca2+ at
this site and dictate the recognition of specific carbohydrate structures. Mutation of these
sites leads to the loss of ligand binding29. The valine amino acid in the CRD of DC-SIGN
has been shown to be involved in the recognition of some ligands, but not all, indicating
that ligands have different, but overlapping, binding sites.
The CRD of DC-SIGN is separated from the transmembrane (TM) region by a neck
domain that consists of seven complete and one incomplete tandem repeat. The neck
domain is required for oligomerization, which regulates carbohydrate specificity. Finally,
a cytoplasmic tail is present, which includes internalization motifs, such as the di-leucine
(LL) motif and the tri-acidic (EEE) clusters, and an incomplete immunoreceptor
tyrosine-based activation motif (ITAM).
DC-SIGN structure
Cytoplasmic domain
LL
EEE
Extracellular domain
Y
TM
Neck
CRD
Val351
DC-SIGN binding site

in the CRD
Asn349
Glu354
Ca2+
Glu347
Asn365
700
carbohydrates, such as Lex, than for mannose-containing carbohydrates60,63. Although DC-SIGN binds complex mannose-containing glycoconjugates that is,
13, 16 mannotriose35,39 high affinity binding
was observed for Lewis blood-group antigens (Lex, Ley,
Lea and Leb) that contain fucose residues in different
anomeric linkages60,63. By contrast, the mannose receptor does not recognize Lex structures34. Sialylation of
Lex, to produce sialyl-Lex a ligand for L-, E- and
P-selectin completely abrogated recognition by DCSIGN, indicating that DC-SIGN has a carbohydrate
specificity that is distinct from that of the selectins
that mediate leukocyte rolling60. Analysis of the binding of these carbohydrate structures to DCs indicated
that despite the presence of many C-type lectins on
DCs, glycoconjugates that contain Lex are preferentially bound by DC-SIGN, whereas 13, 16
mannotriose is also bound by other C-type lectins
(DC-SIGN and mannose receptor). This illustrates
that DC-SIGN is the main receptor expressed by DCs
for recognizing Lex-containing carbohydrate structures, whereas recognition of mannose carbohydrates
can be mediated by more than one C-type lectin on DCs.
However, a more detailed analysis of the C-type lectins
might indicate that these have affinity for carbohydrates
other than mannose.
DC-SIGN: a target for pathogens
The identification of DC-SIGN as a DC-specific adhesion receptor15 indicated that it was identical to the previously cloned HIV-1 envelope-binding C-type lectin,
and so the first pathogen that interacts with DC-SIGN
was discovered29,64. This initiated a detailed investigation
into the function of DC-SIGN as a receptor expressed
by DCs for both macrophage (M) and T-cell (T) tropic
HIV-1, HIV-2 and simian immunodeficiency virus
(SIV)49,6567, and its involvement in the recognition of
other viruses. The fact that DC-SIGN binds distinct
carbohydrate structures, such as mannose-containing
glycoconjugates35,39 and fucose-containing Lewis bloodgroup antigens (Lex, Ley, Lea and Leb)60, indicates that
the carbohydrate specificity of DC-SIGN governs a
broad pathogen-recognition pattern6872 (TABLE 2).
Indeed, DC-SIGN functions as a receptor for several
viruses, including Ebola virus, cytomegalovirus (CMV),
hepatitis C virus and Dengue virus70,7278 (BOX 2).
DC-SIGN recognizes the viral envelope glycoproteins
expressed by these different viruses that contain a relatively large number of N-linked carbohydrates. In particular for HIV-1 and Ebola virus, it has been shown
that differential glycosylation of the envelope glycoproteins affects binding of DC-SIGN and the capacity to
enhance infection of target cells79,80. Other viruses that
express heavily glycosylated glycoproteins on their cell
surface (for example, vesicular stomatitis virus) fail to
interact with DC-SIGN, indicating some degree of specificity in DC-SIGN binding81. Even though it is probable
that high mannose structures on virus-encoded glycoprotein gp120 are recognized by DC-SIGN79,80,82, it has
not been ruled out that proteinprotein interactions
might be involved in binding29.
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Table 2 | DC-SIGN-binding pathogens

Pathogen
Antigen
Carbohydrate structure
Other C-type lectin receptors
HIV-1
gp120
High mannose
Mannose receptor and Langerin
HIV-2
gp120
SIV-1
gp120
Ebola virus
GP
High mannose
Cytomegalovirus
gB
Hepatitis C virus
E1/E2
Dengue virus
gE
Viruses
Bacteria
Helicobacter pylori
LPS
Lewis-x
Klebsiella pneumonae
LPS
Mannose
Mycobacteria tuberculosis
ManLAM
Di-mannose, tri-mannose
Mannose receptor
Mannose receptor
Leishmania pifanoi
LPG
High mannose
Schistosoma mansoni
SEA
Lewis-x
Yeast
Candida albicans
Parasites
gB, glycoprotein B; gE, glycoprotein E; GP, glycoprotein; Langerin, Langerhans-cell-specific C-type lectin; LPG, lipophosphoglycan; LPS,
lipopolysaccharide; ManLAM, mannose-capped lipoarabinomannan; SEA, soluble egg antigen; SIV, simian immunodeficiency virus;
Notably, non-viral pathogens can also interact with

DC-SIGN (TABLE 1). Bacteria such as Helicobacter pylori
and certain strains of Klebsiella pneumonia interact
with DC-SIGN through LPS structures that contain
Lex or mannose, respectively. The mannose-capped
cell-wall component of Mycobacteria tuberculosis
ManLAM (lipoarabinomannan) also interacts with
DC-SIGN60,83. Parasites, such as Leishmania pifanoi 69,
are recognized by DC-SIGN through the mannosecapped surface lipophosphoglycan (LPG)60, or the
Lex-positive Schistosoma mansoni soluble egg antigen
(SEA)63. Yeast, such as Candida albicans, can also be
targeted by DC-SIGN84. So, the carbohydrate profiling
of DC-SIGN enables the prediction of pathogens that
are targeted by this receptor for internalization and
possibly antigen presentation.
The central feature of the pathogens that interact
with DC-SIGN is that they cause chronic infections that
can last a lifetime, and secondly, that manipulation of
the TH1- versus TH2-cell balance by these pathogens is
central to their persistence. A TH1 to TH2 shift is crucial
for the virulence and persistence of Leishmania mexicana. Similarly, the TH2-type immune response to infection with S. mansoni is associated with persistence of the
pathogen, and SEA and its major glycan antigen Lex can
cause a switch towards a TH2-cell-mediated immune
response85. Therefore, these pathogens might target
DC-SIGN not only to infect DCs, but also to shift the
TH1- versus TH2-cell balance towards TH2 in favour of
persistence of pathogen. Notably, expression of DC-SIGN
depends on TH2-type cytokines, linking high expression
of DC-SIGN by DCs to TH2 polarization25. Indeed,
recent results with mycobacteria indicate that some of
these pathogens might specifically target DC-SIGN to
suppress DC function and modulate immune responses,
probably through shifting the TH1- versus TH2-cell

balance68. By contrast, DC-SIGN might also be important in the capture and internalization of these
pathogens for processing and antigen presentation12.
One of the main questions that remains is how
DCs respond to the pathogens that target DC-SIGN.
The interaction of HIV-1 and M. tuberculosis with
DC-SIGN has been investigated in great detail, and is
discussed further.
DC-SIGN as a new type of virus receptor
It is now generally accepted that immature DCs are one

of the first cells that interact with HIV-1 at sites of infection. DCs are thought to capture HIV-1 at entry sites
and transport the virus to lymphoid tissues, in which
DC-bound HIV-1 is efficiently transmitted to CD4+
T cells46,86,87. It was not until the discovery of DC-SIGN
that the molecular mechanism of this interaction
became clear65 (FIG. 2a). DC-SIGN, expressed by DCs in
mucosal tissues65,8890, captures HIV-1 at low titres
through its high-affinity interaction with the HIV-1
envelope glycoprotein gp120 (REF. 65). DC-SIGN does
not facilitate HIV-1 processing by DCs but protects the
virus from intracellular degradation, a process which is
not completely understood65,81. The DC-SIGN-bound
HIV-1 is efficiently transmitted to recipient CD4+ T cells
after co-culture of DCs with CD4+ T cells, which results
in a productive infection of T cells65. DC-SIGN not only
transmits HIV-1, but also enhances the infection of
T cells; at low virus titres T cells are not infected without
the assistance of DC-SIGN in trans46,65 (FIG. 2a). This
indicates that the presence of DC-SIGN is crucial for
rapid and efficient T-cell infection when levels of HIV-1
are low, such as during early infection in vivo. The presence of DC-SIGN-expressing DCs in mucosal tissues
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and the presence of DC-SIGN-positive DC precursors
in the blood that efficiently transmit HIV-1 to T cells91,
indicates that DC-SIGN is a crucial molecule in the
spread of HIV-1 both after sexual transmission and after
contamination with blood92,93.
At high concentrations, HIV-1 can infect DCs that
co-express CD4 and chemokine receptors in culture46,94,95 (FIG. 2a). HIV-1 can replicate in immature and
mature DCs that are interacting with T cells67,96. In particular, the initial quantity of virus that enters the
mucosal tissues might determine whether DCs become
infected by HIV-1 or whether the virus is captured for
efficient trans-infection of T cells65. DC-SIGN might
also function as a cis-receptor for HIV-1, as co-expression of DC-SIGN, CD4 and CC chemokine receptor 5
(CCR5) increases the infection of target cells49,97 (FIG. 2a).
However, it is difficult to exclude the possibility that cells
that seem to be cis-infected by DC-SIGN are actually
trans-infected.
So far, the function of DC-SIGN in HIV-1 infection is
mainly based on in vitro models. However, one in vivo
study shows a potentially enhanced mucosal transmission
of SIVHIV chimaeric virus (SHIV) that contained an
additional glycan at the N-terminal base of the V2 loop
Box 2 | Targeting of DC-SIGN by viruses other than HIV-1

The importance of DC-SIGN (dendritic cell (DC)-specific intercellular adhesion
molecule-grabbing nonintegrin) as an HIV-1 receptor with its specificity for virusencoded envelope glycoprotein leading to an enhanced dissemination of virus initiated
the search for other viruses that interact with DCs through DC-SIGN. As mentioned,
Ebola virus, hepatitis C virus, Dengue virus and cytomegalovirus (CMV) all interact
with DC-SIGN72 (TABLE 1). Alvarez et al.70 showed that DC-SIGN can function as a
cell-entry factor for Ebola virus a highly lethal virus that is responsible for several
outbreaks of haemorrhagic fever. Moreover, immature DCs captured Ebola-virus
pseudotyped particles that were subsequently transmitted to recipient cells. The
expression of DC-SIGN by primary target cells for Ebola virus indicates that DC-SIGN
might be involved early in infection with Ebola virus70,93.
DC-SIGN also functions as a receptor for human CMV72, which is a ubiquitous
pathogen in humans that causes lifelong infection with reactivation episodes. DCs
efficiently capture CMV through DC-SIGN, and the virus is protected from degradation
and subsequently transmitted to permissive cells, similar to HIV-1 (REF. 72). In contrast to
HIV-1, but similar to Ebola virus, DC-SIGN also mediates the actual infection of DCs by
CMV72. Several studies have shown that infection with CMV alters the function of DCs:
CMV-infected DCs have decreased antigen-presentation and differentiation
capacities110,111. The observed transient immunosuppression in CMV infections might
result from virus-mediated interference of DC function. By promoting DC-mediated
trans-infection of target cells, as well as infection of DCs, DC-SIGN might, in addition to
its role in virus propagation, be involved in CMV-modulated immune responses.
Recently, it was shown that DC-SIGN was an important receptor for infection of
human DCs with Dengue virus. In natural infection, DCs are targeted by the mosquito
vector into the skin during a blood meal. DCs were known to support infection with
Dengue virus, but infection does not result in enhanced immune activation. Similar to
CMV, Dengue virus infects DCs themselves; low virus titres are sufficient for capture
by DC-SIGN and for the infection of DCs. Moreover, DC-SIGN enhances the infection of
permissive cells, thereby promoting the spread of virus73. The unique contribution
of DC-SIGN in HIV-1 transmission is further highlighted by the ability of isolated
DC-SIGN-positive blood DCs to transmit HIV-1 to T cells, whereas DC-SIGN-negative
blood DCs lack this ability91, despite the fact that these DC-SIGN-negative blood DCs
express other putative HIV-1-binding C-type lectins112. These subsets of DCs that are
present in the blood might also be targets for other viruses, such as Dengue virus.
702
of SHIV-encoded gp120 that resulted in enhanced binding to DC-SIGN79. Rhesus macaque DC-SIGN is highly
homologous to the human homologue, and the macaque
homologue can function as a trans-receptor for HIV-1
in a similar way to human DC-SIGN98100. Also, the primate DC-SIGN homologues are abundantly expressed
in lymphoid tissues, such as the lymph nodes, as well as
in the mucosal tissues involved in sexual transmission
of HIV-1 (REFS 98101), indicating that primate models
could be used to dissect further the role of DC-SIGN in
the transmission and pathogenesis of infection with
immunodeficiency viruses.
Dendritic cells: a hiding place for HIV-1
Whereas DC-SIGN-bound antibody (and presumably

ligands) are internalized into lysosomal compartments
for processing and presentation to T cells12, whole
DC-SIGN-bound HIV-1 particles are stable and retain
their infectivity for prolonged periods65. Several studies
indicate that DC-SIGN-bound HIV-1 hides in the DC,
close to the cell membrane, without being degraded.
Indeed, HIV-1 is internalized after binding to DC-SIGN
into non-lysosomal acidic organelles and this internalization is crucial for the DC-SIGN-mediated enhancement of T-cell infection81 (FIG. 2a). Neutralization of the
pH of the HIV-1-containing compartments or prevention of internalization by deletion of the DC-SIGN cytoplasmic tail abrogates DC-SIGN-mediated enhanced
trans-infection of T cells81 and indicates that internalization of the HIV-1 particle processed in a infectious
form is essential for the infection of T cells. The
clathrin-dependent sorting pathway probably mediates
DC-SIGN endocytosis and recycling through recognition of the di-leucine motif. Clathrin-independent
pathways might also be used during virus-induced
DC-SIGN internalization.
The function of DC-SIGN in the transmission of
HIV-1 depends on its cellular context74. DC-SIGN
expressed by DCs or the monocytic cell line THP-1, but
not by 293, HOS and K562 cells, internalize and retain
HIV-1 in a highly infectious state for more than 5 days
to infect T cells in trans65,81,102. This indicates that HIV-1
can only hide for prolonged periods in DC-like cells,
due to an altered HIV-1-induced endocytic routing
when targeted to DC-SIGN. The question remains as to
how intact HIV-1 virions escape targeting to lysosomes,
as occurs for other internalized DC-SIGN ligands12, and
how these virions protect themselves from degradation
and processing.
The process by which DC-SIGN enhances efficient
infection of cells in trans through their CD4chemokine
receptor complex still remains unclear. Binding of gp120
to DC-SIGN might induce a conformational change in
gp120 that enables a more efficient interaction with CD4
and/or the chemokine receptor, and subsequent membrane fusion with T cells66,103,104. Alternatively, binding of
virus particles to DC-SIGN might focus or concentrate
the virus particles at the surface of the DC, and so might
increase the probability that entry will occur after binding to the CD4 and co-receptor complex on target cells.
DC-SIGN-bound virions might accumulate in selective
REVIEWS
membrane microdomains. It will be interesting to
determine whether DC-SIGN accumulates in lipid-raft
membrane domains, which are known to be enriched
in virus receptors. In relation to this, it was recently
shown that HIV-1 and its receptors are recruited to
the DCT-cell junction, indicating that through cell
contact with T cells DCs recycle HIV-1 to the membrane to concentrate locally with CD4, co-receptors and
the adhesion molecule leukocyte function-associated
antigen 1 (LFA1), to facilitate transmission to T cells105.
Although HIV particles were found to be internalized
in DCs, no DC-SIGN seemed to concentrate at the
Transmission to T cells
HIV-1
CD4
CCR5
DC-SIGN
DC
T cell
DC infection
c
MHC
class II
Antigen presentation
T cell
MHC
class II
HIV-1
MHC I/II
TCR
Figure 2 | HIV-1 subverts intracellular processing by dendritic cells through DC-SIGN. a | DC-SIGN (dendritic cell (DC)specific intercellular adhesion molecule-grabbing nonintegrin) is expressed by immature DCs in mucosal tissues and lymph nodes,
and by DC precursors in the blood. HIV-1 is captured by DC-SIGN that is expressed by DC precursors in the blood after infection or
by immature DCs at mucosal entry sites during sexual transmission. DC-SIGN-bound HIV-1 enters the cell, but escapes
internalization into lysosomal compartments and recycles back to the cell surface. By hiding intracellularly in DCs, HIV-1 is protected
during migration to the lymphoid tissues. On arrival at lymphoid tissues, DCs transmit HIV-1 to CD4+ T cells in trans, resulting in
productive HIV-1 infection of CD4+ T cells. b | High concentrations of HIV-1 allow viral infection of DCs that results in the production
of HIV-1 by DCs, which subsequently infect T cells. Sequestration of HIV-1 by DC-SIGN can allow cis-infection of DCs by presenting
the infectious virus to CD4 and co-receptors to allow efficient infection of DCs. c | C-type lectins function as antigen receptors to
internalize antigen into lysosomes to enhance antigen presentation by MHC class I and II molecules. It remains to be determined
whether capture of HIV-1 by C-type lectins results in the activation of DCs and presentation of viral antigen by MHC molecules.
CCR5, CC chemokine receptor 5; TCR, T-cell receptor.
REVIEWS
DCT-cell junction where the infectious synapse was
formed. Surprisingly, HIV-1 relocated to the cellcell
border within 1 hour after initial contact with T cells105.
Studies have shown that DCs might also be infected
by HIV-1, although less efficiently than T cells96,106108.
In infected DCs, HIV-1 might interfere with the intracellular trafficking of DC-SIGN through the action of
the HIV-1-encoded Nef protein67. Expression of Nef
after infection of immature DCs reduces DC-SIGN
internalization and increases its cell-surface expression,
thereby facilitating increased cell adhesion and transmission of virus to T cells67. However, other reports
show that this might only occur in certain immature
DC subsets109. The high affinity of DC-SIGN for gp120
compared with CD4 might also lead to competition
between the two cell-surface receptors for HIV-1. The
fact that DCs express high levels of DC-SIGN and low
levels of CD4 might result in efficient binding to
DC-SIGN and might markedly reduce fusion of the
virus envelope97. Future experiments will determine the
molecular mechanism by which DC-SIGN enhances
the infection of T cells, and will elucidate whether a
diversity in multimerization and membrane organization of DC-SIGN are instrumental for its function as a
trans-receptor for HIV-1.
Other HIV-1 trans-receptors
C-type lectins as trans-receptors. DCs express many

other C-type lectins besides DC-SIGN, such as Langerin
and the mannose receptor, that have specificity for mannose-containing carbohydrates present on HIV-1encoded gp120, and have been shown to bind gp120
(REFS 112115). So far, it has only been shown that the
mannose receptor expressed by macrophages, similar to
DC-SIGN, can capture HIV-1 and transmit HIV-1
in trans to permissive T cells116, but it can not be
excluded that other C-type lectins are also involved.
Interestingly, HIV-1 bound to the mannose receptor on
macrophages has a lower half-life than unbound HIV-1,
and no transmission occurred beyond 24 hours after
initial capture of the virus116. The finding that the
longevity of HIV-1 when captured by DC-SIGN exceeds
5 days, indicates that the internalization routes are
different for the mannose receptor and DC-SIGN.
The lower half-life of HIV-1 when captured by the mannose receptor could also be attributed to the fact that
macrophages that express high levels of the mannose
receptor, but do not express DC-SIGN, internalize and
route infectious HIV-1 particles differently from DCs.
Interestingly, on monocyte-derived immature DCs,
DC-SIGN is the main HIV-1 receptor despite co-expression of the mannose receptor65. However, the levels
of expression of different C-type lectins by DC subsets
in vivo might be instrumental in determining which
C-type lectin captures HIV-1, how HIV-1 is intracellularly routed and for how long HIV-1 will survive or be
degraded in the DC for presentation to T cells. The fact
that both DC-SIGN and the mannose receptor recognize HIV-1-encoded gp120 does not necessarily mean
that both receptors bind to a similar site in gp120, as the
carbohydrate specificity of DC-SIGN and the mannose
704
receptor differ34. At present, data showing that C-type

lectins other than DC-SIGN and the mannose receptor
can transmit HIV-1 in trans are lacking112,117. The finding that DC-SIGN- and mannose-receptor-negative
DCs exist in vivo indicates that other C-type lectin
receptors might be used by HIV-1 to hide in DCs.
However, these HIV-1 binding C-type lectins might
have a different function in HIV-1 pathogenesis. They
might be required for the capture and processing of
HIV-1, and for efficient antigen presentation, as DCs can
capture and present antigens from HIV-1 to both CD4+
and CD8+ T cells118 (FIG. 2b). It will be interesting to find
out whether different subsets of DCs that express a different array of C-type lectins handle a pathogen such as
HIV-1 differently, leading to immune escape and spread
of HIV, or to immune activation through processing and
presentation of the virus.
Proteoglycans as trans-receptors. Adhesion receptors,
such as LFA1, ICAM1 and heparan-sulphate proteoglycan (HSPG), have been shown to promote HIV-1
adsorption and infectivity119,120. The presence of both
ICAM1, which is exposed at the surface of the virus,
and LFA1, which is expressed by T cells, increases the
attachment of HIV-1. Moreover, expression of adhesion
receptors facilitates cellcell interactions and thereby
increases transmission of the virus. In addition to
C-type lectins, proteoglycans have been reported
to capture HIV-1 (REF. 102). Syndecan an HSPG that
is expressed by the endothelial lining of the vasculature
has recently been shown to capture HIV and function as a trans-receptor for infection of naive permissive
T cells that interact with the endothelial cells102.
Removal of cell-surface HSPG using heparitinase
diminishes both HIV attachment to and infectivity of
permissive cells121,122. The adsorption of HIV-1 is mediated by the binding of gp120 to the heparan-sulphate
chains of syndecan. Although syndecan does not substitute for HIV-entry receptors, it enhances the transinfection of a broad range of primate lentiviruses, in a
similar way to DC-SIGN. Syndecan also preserves
virus infectivity for at least a week, whereas unbound
virus loses its infectivity in less than a day102. The mechanism by which syndecan retains HIV-1 infectivity is
not known. Analogous to DC-SIGN, it might rapidly
internalize and hide the virus in an intracellular compartment. Alternatively, the syndecan-enhanced
endurance of HIV might be explained by the long
anionic linear heparan-sulphate chains that protect
HIV from proteolytic degradation.
Mycobacteria subvert DC-SIGN function
As mentioned, several studies have shown that other

non-viral pathogens also target DC-SIGN to infect
DCs6972. Most notable, are the distinct mechanisms
by which these pathogens subvert the function of
DC-SIGN to escape immune surveillance123. In particular, the interaction of mycobacteria with DC-SIGN is
highlighted here as an example of the signalling events
of C-type lectins that alter TLR-mediated activation
of DCs.
REVIEWS
a
M. tuberculosis
DC-SIGN
Mannose
receptor
ManLAM
secretion
DC
b Low ManLAM
TLR
DC-SIGN
NF-B
TLR
Increased expression of
CD80, CD83 and CD86
DC maturation
Inflammatory cytokine production
Immune activation
c High ManLAM
TLR
NF-B
Reduced expression of
CD80, CD83 and CD86
DC-SIGN
Inhibition of DC maturation
Increased production of
IL-10 immune suppression
Figure 3 | Mycobacteria tuberculosis target DC-SIGN through ManLAM to suppress

cellular immune responses mediated by dendritic cells. a | DC-SIGN (dendritic cell
(DC)-specific intercellular adhesion molecule-grabbing nonintegrin) captures Mycobacteria
tuberculosis by binding the mannose-capped cell-wall component lipoarabinomannan
(ManLAM). M. tuberculosis are targeted to the late endosomes/lysosomes, whereas HIV-1
escapes internalization to lysosomal compartments (FIG. 2a). M. tuberculosis infects
macrophages through the mannose receptor and/or DCs through DC-SIGN. Macrophages/DCs
that are infected with M. tuberculosis secrete the virulence factor ManLAM that binds to DC-SIGN
on DCs that are attracted to the inflammatory site. b | Recognition of M. Tuberculosis by Toll-like
receptors (TLRs) expressed by DCs results in the activation of nuclear factor-B (NF-B), leading
to the activation/maturation of DCs, as observed by increased expression of co-stimulatory
molecules CD80, CD83 and CD86. DC maturation leads to the production of inflammatory
cytokines and immune activation to enhance T-cell responses to eliminate the pathogen.
c | Increased secretion of ManLAM by infected macrophages or DCs targets DC-SIGN and
results in inhibitory signals that interfere with the TLR-activating stimuli that lead to DC maturation.
The ManLAMDC-SIGN interaction results in inhibition of DC maturation and induction of the
immunosuppressive cytokine interleukin-10 (IL-10), thereby preventing an efficient cellular immune
response against M. tuberculosis infection.
M. tuberculosis represents a worldwide health risk

and immunosuppression is a particular problem in
M. tuberculosis infections. Mycobacteria are potent
inducers of TH1-cell responses and mycobacterial
components have often been shown to stimulate the
expression of co-stimulatory molecules and the production of IL-12 by DCs through TLR2 and TLR4 (REF. 124).
As long as the immune system remains competent, the
M. tuberculosis is normally controlled, yet complete
eradication of the pathogen does not occur. When the
immune response is impaired, active disease can
develop, normally through reactivation of quiescent
organisms or in some cases through re-infection.
Although alveolar macrophages are the main targets of
infection by mycobacteria, DCs are important for the
cellular immune response and DC-SIGN-expressing
DCs have been identified in the airway mucosa, in particular at the submucosal and interstitial sites of the
respiratory tract71,125.
DC-SIGN binds strongly to mycobacteria such as
M. tuberculosis and M. bovis bacillus CalmetteGurin
(BCG) through their mannose-capped cell-wall component ManLAM68,83,126, but does not bind to LAM that
lacks the mannose cap (AraLAM) (FIG. 3a). This is
intriguing because ManLAM is abundant in slow growing virulent mycobacteria, such as M. tuberculosis and
M. leprea, whereas AraLAM is abundant in fast growing
atypical, avirulent mycobacteria, such as M. smegmatis,
M. fortuitum and M. chelonae68,71. DC-SIGN binds
specifically to the dimeric and trimeric mannose
residues in ManLAM. DC-SIGN presumably does not
recognize M. avium, in which ManLAM is capped
with single mannose residues83, which correlates with
the specificity of DC-SIGN for di- and tri-mannose
structures. It is possible that M. avium will be recognized
by the mannose receptor expressed by macrophages
and DCs.
For DCs, DC-SIGN is the main receptor for
mycobacteria68. Although immature DCs also express
high levels of the receptors mannose receptor127,
CD11b and CD11c71, which have previously been
reported to mediate the binding of mycobacteria by
macrophages128,129, DC-SIGN-specific antibodies, in
contrast to mannose-receptor-specific antibodies,
inhibit the interaction of DCs with both M. bovis BCG
and ManLAM by more than 80%68. Recent findings
indicate that although the mycobacteria end up in the
phagosomal compartments, the function of DCs is
modulated by M. tuberculosis68,124. Internalization of
AraLAM by the mannose receptor allows lysosomal
targeting and presentation to T cells by CD1b molecules45. In considering DCs as host cells for M. tuberculosis, M. tuberculosis is captured and internalized by
DC-SIGN to lysosomal compartments that are lysosome-associated membrane protein 1 (LAMP1) positive68,71. It is possible that mycobacteria-containing
phagosomes mature to late endosomes/lysosomes in
DCs, resulting in degradation, whereas in macrophages,
mycobacteria arrest the phagosome maturation at an
early endosomal stage, thereby promoting the growth
of mycobacteria.
REVIEWS
ManLAM
M. tuberculosis
Yeast
Dectin-1
TLR2
TLR4
DC-SIGN
ITAM
ITAM
IL-12
TNF
IL-10
DC-maturation block
Immune activation
Immune suppression
Figure 4 | Model for C-type lectin and Toll-like receptor collaboration. The yeast
component zymosan is recognized simultaneously by the C-type lectin dectin-1 and Toll-like
receptor 2 (TLR2). Together, these receptors facilitate inflammatory responses T helper 1 (TH1)cell responses to the captured particle. Cytokine responses that are triggered by TLRs are
enhanced by dectin-1 ligation and depend on intracellular signals that are generated through the
immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic tail of dectin-1. By
contrast, other C-type lectin and TLR pairs, such as DC-SIGN and TLR4 might inhibit each other
after the recognition of Mycobacterium tuberculosis. Ligation of DC-SIGN by the M. tuberculosis
virulence factor mannose-capped cell-wall component lipoarabinomannan (ManLAM) reduces
TLR4-triggered DC maturation and enhances the production of interleukin-10 (IL-10) favouring a
TH2-cell-mediated response and survival of the pathogen. TNF, tumour-necrosis factor.
Cross talk between C-type lectins and TLRs. Targeting of

DC-SIGN by ManLAM results in an altered immune
response through signalling between C-type lectins and
TLRs68,124 (FIG. 3b). Pathogens might exploit this function
of C-type lectins to interfere with TLR signalling, thereby
modulating DC-dependent immune responses12,42.
Binding of immature DCs to the mycobacterial component ManLAM blocks LPS-induced secretion of IL-12
(REF. 124). The study indicates that binding of ManLAM
to immature DCs interferes with TLR4 signalling, as
LPS signalling is mediated through TLR4 (REF. 130). The
cell-wall component ManLAM, which is considered to
be a virulence factor, is also secreted in vivo by macrophages that are infected with M. tuberculosis131,132, indicating that mycobacteria might specifically secrete
ManLAM to interfere with the immune function of
bystander DCs (FIG. 3a).
In a study by Nigou et al.124, the mannose receptor
was implicated as the C-type lectin that binds
ManLAM. However, recent work shows that ManLAM
inhibits LPS-induced DC maturation by interacting
with DC-SIGN, as LPS-induced DC maturation in the
presence of ManLAM is fully restored by inhibiting the
DC-SIGNManLAM interaction with specific antibodies68. A more physiological function for this interaction
was shown using M. bovis BCG68. Viable M. bovis BCG
induce the maturation of DCs68, probably through
TLR2 and TLR4 signalling133. Similarly, as observed
with LPS, ManLAM specifically blocked the M. bovis
BCG-induced maturation of DCs68 (FIG. 3b). The inhibition of DC maturation caused by ManLAM binding to
DC-SIGN could be fully restored by antibodies specific
for DC-SIGN68. This illustrates that DC-SIGN, after
binding ManLAM, delivers a signal that interferes with
the M. bovis BCG-induced DC-maturation signals
706
presumably generated by TLR4. Furthermore, the binding of ManLAM to DC-SIGN induces the production of
the anti-inflammatory cytokine IL-10 by LPS-activated
DCs68. The inhibition of DC maturation and the induction of IL-10 might contribute to the virulence of
mycobacteria; immature DCs and IL-10-treated DCs
are not only less efficient at stimulating T-cell responses,
but also induce a state of antigen-specific tolerance134.
The fact that DCs do not support the growth of
mycobacteria due to IL-10-induced reversion of DC
maturation135,136 indicates that pathogen recognition by
DC-SIGN might modulate DC-induced immune
responses, shifting the balance from immune activation
towards impairment of immune responses, which
would be beneficial to pathogen survival (FIG. 3b). The
balance between immune activation and immune suppression is, in that case, tightly regulated by the level of
TLR activation and the occupancy of C-type lectins.
Activation of TLRs by pathogen products is beneficial
for immune activation, but this can be directed toward
immune suppression when C-type-lectin receptors,
such as DC-SIGN, are fully occupied. How DC-SIGN
signals are propagated in DCs is not yet clear, but the
presence of immunoreceptor tyrosine-based activation
motifs (ITAMs) in its cytoplasmic tail indicate that
DC-SIGN is capable of direct signalling42.
Both DC-SIGN and dectin-1 contain ITAMs, whereas
DCIR contains an immunoreceptor tyrosine-based
inhibitory motif (ITIM)11,42,137,138. The function of these
activating or inhibitory signalling motifs is not yet clear,
but the finding that pathogen recognition by lectins, such
as DC-SIGN, inhibits intracellular signalling processes
that are initiated by TLR activation68,139,140 indicates that
other C-type lectins could have opposing effects.
Surprisingly, two new studies have shown that other
C-type-lectin receptors cross talk with TLRs after the
simultaneous recognition of pathogen. The C-type
lectin dectin-1 reported to be a receptor for the yeast
component zymosan acts together with TLR2 to
enhance the production of IL-12 and tumour-necrosis
factor (TNF) by DCs, facilitating a TH1-cell response139,140
(FIG. 4). These studies showed that the cytoplasmic tail
of dectin-1, and in particular the ITAM, is involved in
generating enhanced stimulatory capacity. Notably,
DC-SIGN also contains an ITAM, yet when targeted by
M. tuberculosis, the immune response is driven towards
immune suppression by the induction of IL-10 production by DCs and the inhibition of DC maturation.
These studies show that the collaborative recognition of
distinct microbial components by different classes of
innate immune receptors (C-type lectins and TLRs) is
crucial for orchestrating inflammatory or inhibitory
responses. The balance between TLR stimulation and
C-type lectin occupation might fine-tune regulatory
mechanisms to allow appropriate immune responses.
The inflammatory consequence of this recognition
depends on the repertoire of receptors that are expressed
and the functional cooperation between the signals
that are generated downstream of receptor activation.
However, some pathogens seem able to manipulate this
balance, resulting in immune suppression, for example
REVIEWS
by the secretion and production of large quantities
of soluble factors, such as ManLAM, that target
DC-SIGN68
Concluding remarks
Recent studies clearly show that DC-SIGN is a pathogen

receptor expressed by DCs that might be involved in the
dissemination and immunosuppression of various
infectious pathogens. Although as a C-type lectin on
DCs DC-SIGN functions as an antigen receptor to target antigens to lysosomal compartments for presentation to T cells, viral pathogens seem to target DC-SIGN
for transmission, whereas non-viral pathogens, such
as mycobacteria, modulate DC-induced immune activation through DC-SIGN. It will be important to
understand the molecular mechanism by which HIV-1
and other viruses that are captured by DC-SIGN hide
in DCs and escape the processing machinery and subsequent immune activation. Further work is required
to dissect the mechanism by which non-viral pathogens
that target DC-SIGN, for example through the mycobacterial product ManLAM, induce their immunosuppressive effect on DCs, and how they shift the balance
between TLR and C-type-lectin signalling. Also, the signalling properties of DC-SIGN that result in the inhibition of intracellular signalling of TLR deserve further
study, and it will be important to understand whether
other C-type lectins can also behave in this way. It
remains to be answered whether, in addition to HIV-1,
other viruses suppress DC functions by targeting
DC-SIGN. The immunosuppressive setting that characterizes both CMV and HIV-1 infections indicates that
such a mechanism of immunomodulation might exist.
Indeed, shedding of virus-encoded envelope glycoproteins might reflect the secretion of ManLAM and might
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Acknowledgements
We thank all former and present members of our group, including our
collaborators whose work has helped shape the ideas. We thank
A. Engering and S. van Vliet for critical reading of the manuscript. We
are grateful to the Netherlands Organization for Scientific Research,
the AIDS foundation, the Dutch stomach, kidney, liver organization
and the Dutch Cancer Foundation for their financial support.
Online links
DATABASES
The following terms in this article are linked online to:
LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
BDCA2 | CCR5 | CD205 | CD206 | CD207 | CD209 | CD4 |
CLEC1 | DCAL1 | DCIR | dectin-1 | GM-CSF | gp120 | ICAM2 |
ICAM3 | IFN- | IL-4 | IL-10 | IL-12 | LFA1 | Nef | TLR2 | TLR4 |
TLR6 | TLR7 | TLR9
FURTHER INFORMATION
Consortium for functional glycomics:
http://web.mit.edu/glycomics/consortium
Access to this interactive links box is free online.
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DC-SIGN: ESCAPE MECHANISM

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IL-12 production by DCs, whereas the hyphal form

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2003 Nature Publishing Group

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well as in lymph nodes15,24. After DC maturation, the

2003 Nature Publishing Group

C-type lectins are not only involved in the recognition

Table 1 | Expression of C-type lectins and Toll-like receptors by DCs

NATURE REVIEWS | IMMUNOLOGY

and might have a role in autoimmunity50. DC-SIGN

Understanding the exact specificity of C-type lectins for

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2003 Nature Publishing Group

Box 1 | C-type lectins: structure,specificity and function

DC-SIGN binding site

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2003 Nature Publishing Group

Table 2 | DC-SIGN-binding pathogens

Other C-type lectin receptors

Mannose receptor and Langerin

Notably, non-viral pathogens can also interact with

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probably through shifting the TH1- versus TH2-cell

It is now generally accepted that immature DCs are one

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2003 Nature Publishing Group

Box 2 | Targeting of DC-SIGN by viruses other than HIV-1

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Whereas DC-SIGN-bound antibody (and presumably

2003 Nature Publishing Group

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2003 Nature Publishing Group

C-type lectins as trans-receptors. DCs express many

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receptor differ34. At present, data showing that C-type

As mentioned, several studies have shown that other

2003 Nature Publishing Group

Figure 3 | Mycobacteria tuberculosis target DC-SIGN through ManLAM to suppress

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M. tuberculosis represents a worldwide health risk

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2003 Nature Publishing Group

Cross talk between C-type lectins and TLRs. Targeting of

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2003 Nature Publishing Group

Recent studies clearly show that DC-SIGN is a pathogen

Banchereau, J. & Steinman, R. M. Dendritic cells and the

interfere with bystander DC functions. By contrast,

13. Sallusto, F., Cella, M., Danieli, C. & Lanzavecchia, A.

NATURE REVIEWS | IMMUNOLOGY

21. Valladeau, J. et al. Langerin, a novel C-type lectin specific to

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2003 Nature Publishing Group

53. Grakoui, A. et al. The immunological synapse: a molecular

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76. Pohlmann, S. et al. Hepatitis C virus glycoproteins interact

2003 Nature Publishing Group

116. Nguyen, D. G. & Hildreth, J. E. Involvement of macrophage

NATURE REVIEWS | IMMUNOLOGY