You are on page 1of 15

REVIEWS

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-γ (IFN-γ), 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

NATURE REVIEWS | IMMUNOLOGY

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,

VOLUME 3 | SEPTEMBER 2003 | 6 9 7

© 2003 Nature Publishing Group

whereas the mannose receptor and DEC205 contain eight and ten CRDs. intestine. Many different C-type lectins expressed by DCs have been described11. DEC205 (CD205)14. TLR4 and TLR6. the mannose receptor and MGL1 form trimers.com/reviews/immunol © 2003 Nature Publishing Group . Expression of TLRs and C-type lectins. and the production of cytokines. Monocytederived DCs and interstitial DCs express the highest diversity of C-type lectins. which is involved in the capture of different pathogens. indicating a preferential TH2-cell-driven expression of DC-SIGN.28). For the recognition of microorganisms. After recognition by TLRs a signal-transduction cascade is induced. rectum. DC-SIGN (CD209)15. Myeloid DCs express TLR2. Langerin and BDCA2 recognize distinct mannose structures that differ in branching and spacing. as well as in the mucosal tissues by interstitial DCs in the lungs. The valine residue in the CRD of DC-SIGN has been shown to be involved in the recognition of some ligands. and internalize pathogens for degradation in lysosomal compartments to enhance antigen processing and presentation by DCs11.REVIEWS 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-κB ↑ Co-stimulatory and adhesion molecules ↑ Cytokine production DC Figure 1 | C-type lectins and Toll-like receptors: pathogen receptors on dendritic cells.or TH2-cell responses. respectively. 1). Although the subset specificity of most C-type lectins is well characterized for DCs cultured in vitro. whereas DC-SIGN has been shown to form tetramers35. The CRD of DC-SIGN is separated from the transmembrane region by a neck domain. T-cell receptor. whereas the presence of a Gln-Pro-Asp site (present in DC-ASGPR/MGL1) determines specificity for galactose-containing carbohydrate structures30–32. respectively. indicating that ligands have different. but not all. is expressed by dermal DCs. cell adhesion and migration11. After DC maturation. Notably. as 698 | SEPTEMBER 2003 | VOLUME 3 well as in lymph nodes15. 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. the expression of C-type lectins is often reduced. Mutation of these sites leads to the loss of ligand binding29. The C-type lectin DC-SIGN. 17). whereas plasmacytoid DCs express BDCA2 and dectin-1. Reflecting the large variety of C-type lectin expression by monocyte-derived DCs and interstitial DCs. leading to DC maturation. Expression of DC-SIGN is mainly induced by IL-4. Internalization by C-type lectins.nature. In particular.12 (FIG. Characteristics of C-type lectins. a large diversity of TLRs is also expressed by these DC subsets26. DC-associated lectin 1 (DCAL1)19. The main function of C-type lectins expressed by DCs is to interact with conserved molecular patterns that are shared by a large group www. whereas the mannose receptor is mainly induced by granulocyte–macrophage colony-stimulating factor (GM-CSF)25. which are both type I transmembrane proteins11. C-type lectins are expressed by immature DCs in the skin or mucosal tissues. but overlapping. such as the mannose receptor (CD206)13. The presence of a Glu-Pro-Asn site in the CRD predicts specificity for mannose-containing carbohydrate structures. Most C-type lectins expressed by DCs are type II transmembrane proteins (BOX 1) with the exception of the mannose receptor and DEC205. which could explain their distinct carbohydrate-binding specificities39. DCs are specialized to respond to specific microorganisms by expressing distinct sets of TLRs and C-type lectins. C-type lectin receptor 1 (CLEC1)20. 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. mannose receptor. By contrast. DC-SIGN is frequently co-expressed with the mannose receptor. Oligomerization of lectin domains has been shown to alter the affinity and specificity of carbohydrate recognition38. blood DC antigen 2 (BDCA2)16. immature dendritic cells (DCs) express Toll-like receptors (TLRs) and C-type lectins that bind specific pathogen components and carbohydrate structures. CD207)21 and DCasialoglycoprotein receptor (DC-ASGPR)22/macrophage galactose N-acetyl-galactosamine specific lectin 1 (MGL1)23 (TABLE 1).15. such as cell signalling. which through the activation of nuclear factor-κB (NF-κB) results in the upregulation of expression of costimulatory molecules and adhesion molecules. dectin-1 (REF. whereas plasmacytoid DCs express TLR7 and TLR9 (REFS 27. Many of these C-type lectins have been shown to function as antigen receptors11.33–37. only a few C-type lectins have been identified on DCs from the blood and Langerhans cells. TCR. 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).24. they all contain the GluPro-Asn site in their CRD region13. 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. binding sites. Langerhans-cellspecific C-type lectin (Langerin.All type II C-type lectins contain one carbohydrate recognition domain (CRD)8. cervix and placenta. the co-expression of C-type lectins and TLRs in tissues is still an unexplored field of research. DC immunoreceptor (DCIR)18. Depending on their tissue localization and differentiation state. Despite the fact that DC-SIGN. Langerhans cells specifically express Langerin.22. C-type lectins also recognize carbohydrate structures on self glycoproteins to allow tolerance to self antigens and to mediate cellular processes.

such as the di-leucine (Leu-Leu) motif and the tri-acidic (GluGlu-Glu) clusters42 (BOX 1). which are also members of the C-type lectin family. 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).43. This indicates that cell. it is unknown whether they can route different antigens to different intracellular compartments. Enzymatic removal of the N-linked carbohydrates from ICAM2 and ICAM3 abrogates binding to DC-SIGN29. NATURE REVIEWS | IMMUNOLOGY and might have a role in autoimmunity50. The expression of these enzymes changes during the differentiation and activation of lymphocytes.58. macrophage galactose N-acetyl-galactosamine specific lectin 1. leading to enhanced and efficient antigen presentation that allows low concentrations of antigen to be presented efficiently to T cells46–48 (FIG.44.REVIEWS of microorganisms. dectin-1 and CLEC1) target internalized antigens to lysosomes and MHC class IIpositive late endosomes14.and tissue-specific glycosylation of a glycoprotein (post-translational modification) is mediated by the expression of different glycosyltransferases and glycosidases. DC-SIGN. DCAL. 51). Most of the C-type lectins can function as endocytic receptors as shown by their capacity to internalize lectin-specific antibodies11. DC immunoreceptor. For example. DC-associated lectin 1. Self and non-self recognition by C-type lectins C-type lectins are not only involved in the recognition of pathogens. CLEC1. Toll-like receptor. The transient interaction of DC-SIGN with ICAM3 allows screening of the peptide−MHC complexes by T cells15 and stabilizes the intimate DC–T-cell membrane contact. However. other C-type lectins. respectively. Whereas the mannose receptor recognizes end-standing single mannose branched structures or di-mannose VOLUME 3 | SEPTEMBER 2003 | 6 9 9 © 2003 Nature Publishing Group . DC-SIGN and Langerin have been shown to recognize mannosecontaining carbohydrates. Most C-type lectins that have a tri-acidic cluster (DEC205. 1). Interestingly. to ensure large amounts of antigen uptake.56. In this way. Langerhans-cellspecific C-type lectin. as dictated by branching of the mannose structures. 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. BDCA2. 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. enabling efficient engagement of the T-cell receptor (TCR)15. and functions as a cell-adhesion receptor that regulates DC migration51 and DC–T-cell interactions15.53.41. Both ICAM2 and ICAM3 are heavily glycosylated glycoproteins that potentially contain high mannose-type oligosaccharides57. So far. Langerin. such as the mannose receptor. as internalization of mouse IgG has been shown to lead to antigen presentation to mouse immunoglobulin-specific T cells12. Also. but also might contribute to the capture and presentation of glycosylated self antigens. MGL1. quickly recycle though early endosomes.and tissue-specific glycosylation is a strong regulatory element in DC-SIGNmediated cell–cell interactions. To internalize pathogens most of these C-type lectins contain putative internalization motifs. The mannose receptor. DC-SIGN recognizes the self glycoproteins intercellular adhesion molecule 2 (ICAM2) and ICAM3. such as sialyl-Lewis X (Lex). By contrast. blood DC antigen 2. cell-specific glycosylation of ICAM2 and ICAM3 determines whether the specific carbohydrate structures are recognized by DC-SIGN. TLR. DCIR. but with a different specificity. DC-specific intercellular adhesion molecule-grabbing nonintegrin. DCSIGN. The importance of DC-SIGN–ICAM3 interactions in the initial DC–T-cell contact is emphasized by the potency of DC-SIGN-specific antibodies to inhibit DC–T-cell clustering and DC-induced proliferation of resting T cells15. BDCA2. C-type lectin receptor 1. functioning as cell-adhesion receptors that recognize specific carbohydrate structures. 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. which add or remove specific carbohydrate residues. and internalize these pathogens for processing and antigen presentation. the cargo that is carried by the C-type lectins might determine the intracellular compartment to which C-type lectins route42. resulting in the expression of specific carbohydrate structures55. Because carbohydrates interact specifically with lectins. present on endothelial cells thereby mediating leukocyte rolling and migration55. altered glycosylation of a glycoprotein can modify its recognition by C-type lectins and subsequently influence cell–cell interactions59. there is little evidence for antigen presentation in vivo. 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.45. thereby initiating immune responses against a diversity of microorganisms40. the mannose receptor recognizes lysosome hydrolases. Tissueand cell-specific homing and migration by selectins have been shown to be driven by the expression of a selected set of fucosyltransferases. Although most C-type lectins are endocytic receptors. Cell. DC-SIGN functions similarly to selectins.

By contrast.REVIEWS clusters. The CRD of DC-SIGN is a globular structure consisting of 12 β-strands.80.64. and its involvement in the recognition of other viruses.specificity and function C-type lectins are transmembrane proteins that act as cell-adhesion receptors. two α-helices and three disulphide bridges. cytomegalovirus (CMV). Four amino acids (Glu347.82. 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. it has not been ruled out that protein–protein interactions might be involved in binding29. indicating that ligands have different. The valine amino acid in the CRD of DC-SIGN has been shown to be involved in the recognition of some ligands.63. which regulates carbohydrate specificity. One of these Ca2+ sites is essential for the conformation of the CRD. DC-SIGN recognizes both internal mannose branched structures with a minimum of three mannoses (high mannose) and end-standing di-mannoses15. and an incomplete immunoreceptor tyrosine-based activation motif (ITAM). including Ebola virus. α1→3. whereas α1→3. In particular for HIV-1 and Ebola virus. DC-SIGN functions as a receptor for several viruses. A loop protrudes from the protein surface and forms part of two Ca2+-binding sites. Sialylation of Lex. 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. such as mannose-containing glycoconjugates35. Furthermore. DC-SIGN recognizes the viral envelope glycoproteins expressed by these different viruses that contain a relatively large number of N-linked carbohydrates. HIV-2 and simian immunodeficiency virus (SIV)49.39.34. Other viruses that express heavily glycosylated glycoproteins on their cell surface (for example. binding sites.80. Finally. Lea and Leb)60. to produce sialyl-Lex — a ligand for L-.com/reviews/immunol © 2003 Nature Publishing Group . indicates that the carbohydrate specificity of DC-SIGN governs a broad pathogen-recognition pattern68–72 (TABLE 2). are involved in the regulation of signalling pathways and recognize specific carbohydrate structures that are present on self antigens and pathogens. the mannose receptor does not recognize Lex structures34. indicating that DC-SIGN has a carbohydrate specificity that is distinct from that of the selectins that mediate leukocyte rolling60. α1→6 mannotriose35. www. Here. α1→6 mannotriose is also bound by other C-type lectins (DC-SIGN and mannose receptor). Lea and Leb) that contain fucose residues in different anomeric linkages60. a more detailed analysis of the C-type lectins might indicate that these have affinity for carbohydrates other than mannose. This illustrates that DC-SIGN is the main receptor expressed by DCs for recognizing Lex-containing carbohydrate structures. the recognition of specific carbohydrate structures by DC-SIGN seems to depend on the spacing of the carbohydrate structures on a glycoprotein35. indicating some degree of specificity in DC-SIGN binding81. glycoconjugates that contain Lex are preferentially bound by DC-SIGN. such as Lex.72–78 (BOX 2). and so the first pathogen that interacts with DC-SIGN was discovered29. DC-SIGN (dendritic cell (DC)-specific intercellular adhesion molecule-grabbing nonintegrin) — a prototype type II transmembrane C-type lectin — is depicted. As shown. vesicular stomatitis virus) fail to interact with DC-SIGN. but overlapping. E. Mutation of these sites leads to the loss of ligand binding29. Ley. Analysis of the binding of these carbohydrate structures to DCs indicated that despite the presence of many C-type lectins on DCs. which includes internalization motifs. Screening panels of synthetic glycoconjugates that contain mannose. but not all. 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). galactose or fucose residues and their multimeric derivatives were used to determine further the specificity of C-type lectins60–62. Ley. 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. Glu354 and Asn365) interact with Ca2+ at this site and dictate the recognition of specific carbohydrate structures. such as the di-leucine (LL) motif and the tri-acidic (EEE) clusters. whereas recognition of mannose carbohydrates can be mediated by more than one C-type lectin on DCs. whereas the other Ca2+ site is essential for direct coordination of the carbohydrate structures. Even though it is probable that high mannose structures on virus-encoded glycoprotein gp120 are recognized by DC-SIGN79.nature.63. The neck domain is required for oligomerization. Indeed. hepatitis C virus and Dengue virus70. However.65–67.and P-selectin — completely abrogated recognition by DCSIGN. Although DC-SIGN binds complex mannose-containing glycoconjugates — that is. Asn349. 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 | SEPTEMBER 2003 | VOLUME 3 carbohydrates. than for mannose-containing carbohydrates60.39 and fucose-containing Lewis bloodgroup antigens (Lex. 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. a cytoplasmic tail is present. The fact that DC-SIGN binds distinct carbohydrate structures. 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. This indicated that DC-SIGN has a higher specificity for fucose-containing Box 1 | C-type lectins: structure.39 — high affinity binding was observed for Lewis blood-group antigens (Lex.

One of the main questions that remains is how DCs respond to the pathogens that target DC-SIGN.versus TH2-cell balance68. but also to shift the TH1. that manipulation of the TH1. expression of DC-SIGN depends on TH2-type cytokines. mannose-capped lipoarabinomannan. but also enhances the infection of T cells. recent results with mycobacteria indicate that some of these pathogens might specifically target DC-SIGN to suppress DC function and modulate immune responses. Yeast. soluble egg antigen. the carbohydrate profiling of DC-SIGN enables the prediction of pathogens that are targeted by this receptor for internalization and possibly antigen presentation.versus TH2-cell balance by these pathogens is central to their persistence. are recognized by DC-SIGN through the mannosecapped surface lipophosphoglycan (LPG)60. Langerhans-cell-specific C-type lectin. The DC-SIGN-bound HIV-1 is efficiently transmitted to recipient CD4+ T cells after co-culture of DCs with CD4+ T cells. at low virus titres T cells are not infected without the assistance of DC-SIGN in trans46. a process which is not completely understood65. Notably.88–90. glycoprotein B. DC-SIGN not only transmits HIV-1. So. which results in a productive infection of T cells65.87. captures HIV-1 at low titres through its high-affinity interaction with the HIV-1 envelope glycoprotein gp120 (REF. in which DC-bound HIV-1 is efficiently transmitted to CD4+ T cells46. tri-mannose Mannose receptor ? ? Mannose receptor Leishmania pifanoi LPG High mannose Schistosoma mansoni SEA Lewis-x Yeast Candida albicans Parasites gB. SIV. LPG. such as Leishmania pifanoi 69. Parasites. ManLAM. Langerin.65 (FIG. Notably.versus TH2-cell balance towards TH2 in favour of persistence of pathogen. these pathogens might target DC-SIGN not only to infect DCs. GP. SEA. can also be targeted by DC-SIGN84. Therefore. It was not until the discovery of DC-SIGN that the molecular mechanism of this interaction became clear65 (FIG. such as during early infection in vivo. or the Lex-positive Schistosoma mansoni soluble egg antigen (SEA)63.81. respectively. Bacteria such as Helicobacter pylori and certain strains of Klebsiella pneumonia interact with DC-SIGN through LPS structures that contain Lex or mannose. and is discussed further. non-viral pathogens can also interact with DC-SIGN (TABLE 1). 2a). the TH2-type immune response to infection with S. and SEA and its major glycan antigen Lex can cause a switch towards a TH2-cell-mediated immune response85. glycoprotein. NATURE REVIEWS | IMMUNOLOGY probably through shifting the TH1. such as Candida albicans. The central feature of the pathogens that interact with DC-SIGN is that they cause chronic infections that can last a lifetime. lipopolysaccharide. Similarly. LPS.86. gE. DC-SIGN. Indeed. 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.83. expressed by DCs in mucosal tissues65. By contrast. linking high expression of DC-SIGN by DCs to TH2 polarization25. and secondly. glycoprotein E. DC-SIGN might also be important in the capture and internalization of these pathogens for processing and antigen presentation12. DC-SIGN does not facilitate HIV-1 processing by DCs but protects the virus from intracellular degradation. DCs are thought to capture HIV-1 at entry sites and transport the virus to lymphoid tissues. This indicates that the presence of DC-SIGN is crucial for rapid and efficient T-cell infection when levels of HIV-1 are low. The mannose-capped cell-wall component of Mycobacteria tuberculosis ManLAM (lipoarabinomannan) also interacts with DC-SIGN60. simian immunodeficiency virus. 65). The presence of DC-SIGN-expressing DCs in mucosal tissues VOLUME 3 | SEPTEMBER 2003 | 7 0 1 © 2003 Nature Publishing Group .REVIEWS 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. 2a). mansoni is associated with persistence of the pathogen. lipophosphoglycan. The interaction of HIV-1 and M. A TH1 to TH2 shift is crucial for the virulence and persistence of Leishmania mexicana. tuberculosis with DC-SIGN has been investigated in great detail.

DC-SIGN enhances the infection of permissive cells.94. DC-SIGN might also function as a cis-receptor for HIV-1. it is difficult to exclude the possibility that cells that seem to be cis-infected by DC-SIGN are actually trans-infected. DCs are targeted by the mosquito vector into the skin during a blood meal. DC-SIGN-bound virions might accumulate in selective www. CD4 and CC chemokine receptor 5 (CCR5) increases the infection of target cells49. Also. Alvarez et al. hepatitis C virus. 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. In contrast to HIV-1. Moreover. and how these virions protect themselves from degradation and processing.111. it was shown that DC-SIGN was an important receptor for infection of human DCs with Dengue virus. Dengue virus and cytomegalovirus (CMV) all interact with DC-SIGN72 (TABLE 1). Moreover. 72). DCs efficiently capture CMV through DC-SIGN. DCs were known to support infection with Dengue virus. 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. Alternatively. low virus titres are sufficient for capture by DC-SIGN and for the infection of DCs. and so might increase the probability that entry will occur after binding to the CD4 and co-receptor complex on target cells. The question remains as to how intact HIV-1 virions escape targeting to lysosomes. 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.com/reviews/immunol © 2003 Nature Publishing Group . 702 | SEPTEMBER 2003 | VOLUME 3 of SHIV-encoded gp120 that resulted in enhanced binding to DC-SIGN79. DC-SIGN also functions as a receptor for human CMV72. Indeed. as occurs for other internalized DC-SIGN ligands12. whereas DC-SIGN-negative blood DCs lack this ability91. Similar to CMV. Recently. Ebola virus.102. be involved in CMV-modulated immune responses. due to an altered HIV-1-induced endocytic routing when targeted to DC-SIGN.93. The process by which DC-SIGN enhances efficient infection of cells in trans through their CD4−chemokine receptor complex still remains unclear. So far. binding of virus particles to DC-SIGN might focus or concentrate the virus particles at the surface of the DC. This indicates that HIV-1 can only hide for prolonged periods in DC-like cells. Several studies indicate that DC-SIGN-bound HIV-1 ‘hides’ in the DC. Several studies have shown that infection with CMV alters the function of DCs: CMV-infected DCs have decreased antigen-presentation and differentiation capacities110. DC-SIGN expressed by DCs or the monocytic cell line THP-1.103. DC-SIGN might. and subsequent membrane fusion with T cells66.70 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.96. 2a). one in vivo study shows a potentially enhanced mucosal transmission of SIV−HIV 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. In particular. However. 2a).93. but similar to Ebola virus. 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. Clathrin-independent pathways might also be used during virus-induced DC-SIGN internalization. and the macaque homologue can function as a trans-receptor for HIV-1 in a similar way to human DC-SIGN98–100.95 (FIG. such as the lymph nodes. The clathrin-dependent sorting pathway probably mediates DC-SIGN endocytosis and recycling through recognition of the di-leucine motif. whole DC-SIGN-bound HIV-1 particles are stable and retain their infectivity for prolonged periods65.81. HOS and K562 cells. without being degraded. similar to HIV-1 (REF. These subsets of DCs that are present in the blood might also be targets for other viruses. DC-SIGN also mediates the actual infection of DCs by CMV72. By promoting DC-mediated trans-infection of target cells. As mentioned. 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. as well as infection of DCs. the primate DC-SIGN homologues are abundantly expressed in lymphoid tissues. 2a). However. despite the fact that these DC-SIGN-negative blood DCs express other putative HIV-1-binding C-type lectins112. internalize and retain HIV-1 in a highly infectious state for more than 5 days to infect T cells in trans65.REVIEWS and the presence of DC-SIGN-positive DC precursors in the blood that efficiently transmit HIV-1 to T cells91. The observed transient immunosuppression in CMV infections might result from virus-mediated interference of DC function.104. Rhesus macaque DC-SIGN is highly homologous to the human homologue. close to the cell membrane. the function of DC-SIGN in HIV-1 infection is mainly based on in vitro models. 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.nature. At high concentrations. HIV-1 can infect DCs that co-express CD4 and chemokine receptors in culture46. such as Dengue virus. HIV-1 can replicate in immature and mature DCs that are interacting with T cells67. and the virus is protected from degradation and subsequently transmitted to permissive cells. as co-expression of DC-SIGN. but infection does not result in enhanced immune activation. but not by 293. thereby promoting the spread of virus73. Dengue virus infects DCs themselves. which is a ubiquitous pathogen in humans that causes lifelong infection with reactivation episodes.97 (FIG. The function of DC-SIGN in the transmission of HIV-1 depends on its cellular context74. as well as in the mucosal tissues involved in sexual transmission of HIV-1 (REFS 98−101). 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. in addition to its role in virus propagation. indicates that DC-SIGN is a crucial molecule in the spread of HIV-1 both after sexual transmission and after contamination with blood92. 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. In natural infection. immature DCs captured Ebola-virus pseudotyped particles that were subsequently transmitted to recipient cells.

DCs transmit HIV-1 to CD4+ T cells in trans. 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. Although HIV particles were found to be internalized in DCs. which are known to be enriched in virus receptors. to facilitate transmission to T cells105. By hiding intracellularly in DCs. CCR5. a | DC-SIGN (dendritic cell (DC)specific intercellular adhesion molecule-grabbing nonintegrin) is expressed by immature DCs in mucosal tissues and lymph nodes. 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. NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | SEPTEMBER 2003 | 7 0 3 © 2003 Nature Publishing Group . no DC-SIGN seemed to concentrate at the a Transmission to T cells HIV-1 CD4 CCR5 DC-SIGN DC T cell b 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. co-receptors and the adhesion molecule leukocyte function-associated antigen 1 (LFA1). and by DC precursors in the blood. indicating that through cell contact with T cells DCs recycle HIV-1 to the membrane to concentrate locally with CD4. 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. In relation to this. TCR. T-cell receptor. 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 was recently shown that HIV-1 and its receptors are recruited to the DC–T-cell junction. 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. CC chemokine receptor 5. On arrival at lymphoid tissues.REVIEWS membrane microdomains. but escapes internalization into lysosomal compartments and recycles back to the cell surface. It will be interesting to determine whether DC-SIGN accumulates in lipid-raft membrane domains. resulting in productive HIV-1 infection of CD4+ T cells. DC-SIGN-bound HIV-1 enters the cell. HIV-1 is protected during migration to the lymphoid tissues.

117. other reports show that this might only occur in certain immature DC subsets109. leading to immune escape and spread of HIV. The presence of both ICAM1. proteoglycans have been reported to capture HIV-1 (REF. Syndecan also preserves virus infectivity for at least a week. Alternatively. Interestingly. and LFA1.122. However. in a similar way to DC-SIGN. ICAM1 and heparan-sulphate proteoglycan (HSPG).nature. but it can not be excluded that other C-type lectins are also involved. as DCs can capture and present antigens from HIV-1 to both CD4+ and CD8+ T cells118 (FIG. Surprisingly. which is expressed by T cells. 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. The finding that the longevity of HIV-1 when captured by DC-SIGN exceeds 5 days. HIV-1 relocated to the cell–cell border within 1 hour after initial contact with T cells105. Other HIV-1 trans-receptors C-type lectins as trans-receptors. DCs express many other C-type lectins besides DC-SIGN. Interestingly. have been shown to promote HIV-1 adsorption and infectivity119. 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. 102). Most notable. Analogous to DC-SIGN. such as LFA1. can capture HIV-1 and transmit HIV-1 in trans to permissive T cells116. In infected DCs. which is exposed at the surface of the virus. increases the attachment of HIV-1. that have specificity for mannose-containing carbohydrates present on HIV-1encoded gp120. 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. although less efficiently than T cells96. Expression of Nef after infection of immature DCs reduces DC-SIGN internalization and increases its cell-surface expression. it enhances the transinfection of a broad range of primate lentiviruses.com/reviews/immunol © 2003 Nature Publishing Group . expression of adhesion receptors facilitates cell–cell interactions and thereby increases transmission of the virus. it has only been shown that the mannose receptor expressed by macrophages. internalize and route infectious HIV-1 particles differently from DCs. Although syndecan does not substitute for HIV-entry receptors. Adhesion receptors. 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. However. Moreover. it might rapidly internalize and hide the virus in an intracellular compartment.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. The adsorption of HIV-1 is mediated by the binding of gp120 to the heparan-sulphate chains of syndecan.120. 2b). Mycobacteria subvert DC-SIGN function As mentioned. on monocyte-derived immature DCs. 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. and have been shown to bind gp120 (REFS 112–115). HIV-1 bound to the mannose receptor on macrophages has a lower half-life than unbound HIV-1.REVIEWS DC–T-cell junction where the infectious synapse was formed. several studies have shown that other non-viral pathogens also target DC-SIGN to infect DCs69–72. 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-1.106−108. In addition to C-type lectins. They might be required for the capture and processing of HIV-1. Future experiments will determine the molecular mechanism by which DC-SIGN enhances the infection of T cells. whereas unbound virus loses its infectivity in less than a day102. DC-SIGN is the main HIV-1 receptor despite co-expression of the mannose receptor65. 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. Removal of cell-surface HSPG using heparitinase diminishes both HIV attachment to and infectivity of permissive cells121. So far. The mechanism by which syndecan retains HIV-1 infectivity is not known. Studies have shown that DCs might also be infected by HIV-1. but do not express DC-SIGN. or to immune activation through processing and presentation of the virus. the syndecan-enhanced endurance of HIV might be explained by the long anionic linear heparan-sulphate chains that protect HIV from proteolytic degradation. and no transmission occurred beyond 24 hours after initial capture of the virus116. Proteoglycans as trans-receptors. However. thereby facilitating increased cell adhesion and transmission of virus to T cells67. data showing that C-type lectins other than DC-SIGN and the mannose receptor can transmit HIV-1 in trans are lacking112. 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 finding that DC-SIGN. are the distinct mechanisms by which these pathogens subvert the function of DC-SIGN to escape immune surveillance123. these HIV-1 binding C-type lectins might have a different function in HIV-1 pathogenesis. 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. such as Langerin and the mannose receptor. At present. HIV-1 might interfere with the intracellular trafficking of DC-SIGN through the action of the HIV-1-encoded Nef protein67. indicates that the internalization routes are different for the mannose receptor and DC-SIGN. and for efficient antigen presentation. In particular. as the carbohydrate specificity of DC-SIGN and the mannose 704 | SEPTEMBER 2003 | VOLUME 3 receptor differ34. similar to DC-SIGN. www. 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.

thereby preventing an efficient cellular immune response against M. DC maturation leads to the production of inflammatory cytokines and immune activation to enhance T-cell responses to eliminate the pathogen.71. 124). tuberculosis is captured and internalized by DC-SIGN to lysosomal compartments that are lysosome-associated membrane protein 1 (LAMP1) positive68. inhibit the interaction of DCs with both M. Tuberculosis by Toll-like receptors (TLRs) expressed by DCs results in the activation of nuclear factor-κB (NF-κB). tuberculosis infects macrophages through the mannose receptor and/or DCs through DC-SIGN. as observed by increased expression of co-stimulatory molecules CD80. M. 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. CD11b and CD11c71. Recent findings indicate that although the mycobacteria end up in the phagosomal compartments. For DCs. smegmatis. yet complete eradication of the pathogen does not occur. DCs are important for the cellular immune response and DC-SIGN-expressing DCs have been identified in the airway mucosa.125. resulting in degradation. 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. whereas AraLAM is abundant in fast growing atypical. normally through reactivation of quiescent organisms or in some cases through re-infection. the M. Although immature DCs also express high levels of the receptors mannose receptor127.124. DC-SIGN presumably does not recognize M. tuberculosis68. in which ManLAM is capped with single mannose residues83. It is possible that mycobacteria-containing phagosomes mature to late endosomes/lysosomes in DCs. leprea. such as M. The ManLAM–DC-SIGN interaction results in inhibition of DC maturation and induction of the immunosuppressive cytokine interleukin-10 (IL-10). avirulent mycobacteria. mycobacteria arrest the phagosome maturation at an early endosomal stage. NATURE REVIEWS | IMMUNOLOGY M. tuberculosis secrete the virulence factor ManLAM that binds to DC-SIGN on DCs that are attracted to the inflammatory site. M. When the immune response is impaired. In considering DCs as host cells for M. which have previously been reported to mediate the binding of mycobacteria by macrophages128. thereby promoting the growth of mycobacteria. leading to the activation/maturation of DCs.71. DC-SIGN-specific antibodies. the function of DCs is modulated by M. tuberculosis infection. but does not bind to LAM that lacks the mannose cap (AraLAM) (FIG. tuberculosis. It is possible that M. M. As long as the immune system remains competent. 3a). bovis BCG and ManLAM by more than 80%68. tuberculosis and M. VOLUME 3 | SEPTEMBER 2003 | 7 0 5 © 2003 Nature Publishing Group . avium will be recognized by the mannose receptor expressed by macrophages and DCs. This is intriguing because ManLAM is abundant in slow growing virulent mycobacteria. tuberculosis is normally controlled. fortuitum and M. tuberculosis and M. b | Recognition of M. avium. whereas in macrophages. chelonae68. in contrast to mannose-receptor-specific antibodies. CD83 and CD86 DC maturation Inflammatory cytokine production Immune activation c High ManLAM TLR NF-κB Reduced expression of CD80. bovis bacillus Calmette–Guérin (BCG) through their mannose-capped cell-wall component ManLAM68. which correlates with the specificity of DC-SIGN for di. active disease can develop. tuberculosis are targeted to the late endosomes/lysosomes. 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.REVIEWS a M. in particular at the submucosal and interstitial sites of the respiratory tract71. M. Internalization of AraLAM by the mannose receptor allows lysosomal targeting and presentation to T cells by CD1b molecules45. DC-SIGN binds specifically to the dimeric and trimeric mannose residues in ManLAM. 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).83. 2a).126.129. CD83 and CD86. tuberculosis represents a worldwide health risk and immunosuppression is a particular problem in M.and tri-mannose structures. Although alveolar macrophages are the main targets of infection by mycobacteria. tuberculosis infections. tuberculosis DC-SIGN Mannose receptor ManLAM secretion DC b Low ManLAM TLR DC-SIGN NF-κB TLR Increased expression of CD80. whereas HIV-1 escapes internalization to lysosomal compartments (FIG. Macrophages/DCs that are infected with M. DC-SIGN binds strongly to mycobacteria such as M. DC-SIGN is the main receptor for mycobacteria68. such as M.

Similarly. The study indicates that binding of ManLAM to immature DCs interferes with TLR4 signalling. other C-type lectin and TLR pairs. but the finding that pathogen recognition by lectins. 124).137.nature.140 (FIG.com/reviews/immunol © 2003 Nature Publishing Group . Targeting of DC-SIGN by ManLAM results in an altered immune response through signalling between C-type lectins and TLRs68. such as DC-SIGN. 3b). Pathogens might exploit this function of C-type lectins to interfere with TLR signalling. 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. whereas DCIR contains an immunoreceptor tyrosine-based inhibitory motif (ITIM)11. The fact that DCs do not support the growth of mycobacteria due to IL-10-induced reversion of DC maturation135. Viable M.42. This illustrates that DC-SIGN. Activation of TLRs by pathogen products is beneficial for immune activation.124. for example www. some pathogens seem able to manipulate this balance. after binding ManLAM.132. recent work shows that ManLAM inhibits LPS-induced DC maturation by interacting with DC-SIGN. Surprisingly. is also secreted in vivo by macrophages that are infected with M. The function of these activating or inhibitory signalling motifs is not yet clear. A more physiological function for this interaction was shown using M. TNF. 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 cell-wall component ManLAM. The inhibition of DC maturation caused by ManLAM binding to DC-SIGN could be fully restored by antibodies specific for DC-SIGN68. immature DCs and IL-10-treated DCs are not only less efficient at stimulating T-cell responses. The yeast component zymosan is recognized simultaneously by the C-type lectin dectin-1 and Toll-like receptor 2 (TLR2).138. but this can be directed toward immune suppression when C-type-lectin receptors. Together. these receptors facilitate inflammatory responses — T helper 1 (TH1)cell responses — to the captured particle. inhibits intracellular signalling processes that are initiated by TLR activation68. which would be beneficial to pathogen survival (FIG. The inhibition of DC maturation and the induction of IL-10 might contribute to the virulence of mycobacteria.140 indicates that other C-type lectins could have opposing effects.REVIEWS ManLAM M. ManLAM specifically blocked the M.136 indicates that pathogen recognition by DC-SIGN might modulate DC-induced immune responses.124 (FIG. In a study by Nigou et al. 3b). bovis BCG-induced maturation of DCs68 (FIG. the immune response is driven towards immune suppression by the induction of IL-10 production by DCs and the inhibition of DC maturation. resulting in immune suppression. bovis BCG68. and in particular the ITAM. which is considered to be a virulence factor. are fully occupied. By contrast. tuberculosis. is involved in generating enhanced stimulatory capacity. thereby modulating DC-dependent immune responses12. Binding of immature DCs to the mycobacterial component ManLAM blocks LPS-induced secretion of IL-12 (REF. How DC-SIGN signals are propagated in DCs is not yet clear. the mannose receptor was implicated as the C-type lectin that binds ManLAM. facilitating a TH1-cell response139. 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. indicating that mycobacteria might specifically secrete ManLAM to interfere with the immune function of bystander DCs (FIG. in that case. 3a). bovis BCG induce the maturation of DCs68. tuberculosis131. two new studies have shown that other C-type-lectin receptors cross talk with TLRs after the simultaneous recognition of pathogen. as LPS-induced DC maturation in the presence of ManLAM is fully restored by inhibiting the DC-SIGN−ManLAM interaction with specific antibodies68. 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. 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-1.139. DC-SIGN also contains an ITAM. delivers a signal that interferes with the M. Furthermore. Cross talk between C-type lectins and TLRs. bovis BCG-induced DC-maturation signals 706 | SEPTEMBER 2003 | VOLUME 3 presumably generated by TLR4. but also induce a state of antigen-specific tolerance134. Ligation of DC-SIGN by the M.42. However. Notably. the binding of ManLAM to DC-SIGN induces the production of the anti-inflammatory cytokine IL-10 by LPS-activated DCs68. 130). The balance between TLR stimulation and C-type lectin occupation might fine-tune regulatory mechanisms to allow appropriate immune responses. such as DC-SIGN and TLR4 might inhibit each other after the recognition of Mycobacterium tuberculosis. 3b). as observed with LPS. However. as LPS signalling is mediated through TLR4 (REF. tightly regulated by the level of TLR activation and the occupancy of C-type lectins. shifting the balance from immune activation towards impairment of immune responses. such as DC-SIGN. 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. The balance between immune activation and immune suppression is. These studies showed that the cytoplasmic tail of dectin-1. probably through TLR2 and TLR4 signalling133. 4). tumour-necrosis factor. Both DC-SIGN and dectin-1 contain ITAMs. but the presence of immunoreceptor tyrosine-based activation motifs (ITAMs) in its cytoplasmic tail indicate that DC-SIGN is capable of direct signalling42. yet when targeted by M.

& Steinman. 1973–1983 (1999). 43818–43823 (2001). Exp. one of which is selectively expressed in human dendritic cells.. is an endocytic receptor that induces the formation of Birbeck granules. 7. 19–34 (1998). Akira. Toll-like receptors: key mediators of microbe detection. K. J. thereby facilitating an efficient immune response against these pathogens11. 23. the signalling properties of DC-SIGN that result in the inhibition of intracellular signalling of TLR deserve further study. J. Cell 106. van Kooyk. H. A. 575–585 (2000). 8. T. M. J. Dzionek. Immunol. Relloso. 2. D. Cell. M. Dendritic cells and the control of immunity. Immunol. 22. Cella. differential cell. Further work is required to dissect the mechanism by which non-viral pathogens that target DC-SIGN.and tissuespecific glycosylation might be important for the control of recognition of self antigen. & Hemmi. and their functions in innate and adaptive immunity. The first paper that identified DC-SIGN (dendritic cell (DC)-specific intercellular adhesion moleculegrabbing nonintegrin) as a DC specific C-type lectin that regulates DC-induced T-cell proliferation. F.. 2118–2126 (2002). 4. Immunol. T. Napolitani. 168. Immunol. A.. Trends Cell. 197–216 (2002). Yamamoto. 163. & Irimura. K. J. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. et al. Immunol. 15. E. et al. 168. 13. Willment. 5. 697–704 (2000). 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. and to understand how differential pathogen glycosylation might effect targeting to DC subsets in vivo. H. Med. K. J. Hemmi. 27. Lett. J. D. Am. By contrast. Its unique carbohydrate binding specificity for Tn antigen. J. et al. the initial observation that HIV-1 targets DC-SIGN for dissemination of virus seems to represent a more general mechanism used by other virus and possibly non-viral pathogens. Osawa. S.. L. Immunol. Biol. 26.. F. & Lanzavecchia. 1823–1834 (2001). et al. & Brown. and lead to pathogen elimination or survival. It will be extremely important to identify the carbohydrate specificity of each type of C-type lectin expressed by DCs. Similarly. APCs express DCIR. Jr & Medzhitov. The C-type lectin superfamily in the immune system. 85–95 (2003). Bates. Geijtenbeek. 389–400 (1995). Colonna. N. 128–135 (1996). J. 10. 17. H.. Immunol. S. C-type lectin receptors on dendritic cells and Langerhans cells. Valladeau. 1661–1674 (2000). 191. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. 163. Exp. S. T. J. Identification of DC-SIGN.REVIEWS by the secretion and production of large quantities of soluble factors. Immunity 12. d’Ostiani. in addition to HIV-1. C. M. D. 887–896 (2003). 259–262 (2001). 8. et al. NATURE REVIEWS | IMMUNOLOGY 21. 740–745 (2000). interfere with bystander DC functions. et al. G. R. Immunol. 3388–3393 (2001). M. Also. J. 28. The fact that other C-type lectins can recognize pathogens similar to DC-SIGN and might function as trans-receptors. F. Characterization of the human β-glucan receptor and its alternatively spliced isoforms. Indeed. M. Jarrossay. 673–684 (2000). E. Immunol. Nature 392. Eur. Valladeau. Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. E. Liu. and through different signalling pathways might bias DC-induced T-cell responses either to TH1 or TH2 type. Eur.. 18. Langerin. 16. U. R. et al. for example through the mycobacterial product ManLAM. M. R. Immunol. 14. Immunol. Exp. et al. J. J. Kammerer. 1704–1709 (2002). J. 169. Microbial compounds selectively induce TH1 cell-promoting or TH2 cell-promoting dendritic cells in vitro with diverse TH cell-polarizing signals. Nature 408. A Toll-like receptor recognizes bacterial DNA. C. A.142 will be helpful in determining its importance in vivo. 20. Engering. 77–84 (2002). 19. can recycle and enhance antigen presentation via major histocompatibility complex class II-positive lysosomal compartments. M. N. 156. Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. J. Dendritic cell subsets and lineages. Immunol. E. shedding of virus-encoded envelope glycoproteins might reflect the secretion of ManLAM and might 1.. Toyoshima. 2634–2643 (2002). Dendritic cell-associated lectin-1: a novel dendritic cell-associated. et al. A. Immature human dendritic cells express asialoglycoprotein receptor isoforms for efficient receptormediated endocytosis. such as mycobacteria. The immunosuppressive setting that characterizes both CMV and HIV-1 infections indicates that such a mechanism of immunomodulation might exist. and DC migration and cell adhesion. J. Annu. 168. BDCA-2. Y. 182. Chem. a novel plasmacytoid dendritic cell-specific type II C-type lectin. Danieli. Med. C. J. other pathogens might be captured by DC-SIGN for processing and antigen presentation. 1544–1547 (2001). In conclusion. Janeway. 276. Biol. Med. 11. Implications for initiation of T helper cell immunity in vitro and in vivo. Immunol. C-type lectin-like molecule enhances T cell secretion of IL-4. and anti-inflammatory agents. et al. These studies indicate that DC-SIGN might be a universal target for designing strategies to combat infections with HIV-1. Immunol. viral pathogens seem to target DC-SIGN for transmission. other viruses suppress DC functions by targeting DC-SIGN. 12. 151. 31. et al. Antigen processing for amateurs and professionals. a novel C-type lectin surface receptor containing an immunoreceptor tyrosinebased inhibitory motif. It remains to be answered whether. & Drickamer. modulate DC-induced immune activation through DC-SIGN. de Jong. 194. Induction of direct antimicrobial activity through mammalian toll-like receptors. Suzuki. Molecular characterization of two novel C-type lectin-like receptors. et al. J. Rev. Cell 100. Mahnke. DC-SIGN (CD209) expression is IL-4 dependent and is negatively regulated by IFN.. 2. Rev. whereas non-viral pathogens. 863–869 (2001). M. Biol. This paper highlights DC-subset-specific expression of Toll-like receptors (TLRs) and tailored immune responses. S. and it will be important to understand whether other C-type lectins can also behave in this way. 30. Curr. 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. Recognition of pathogen-associated molecular patterns by TLR family. Mellman.. 20. Samaridis. S. J. Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. mediates antigen capture and is a potent inhibitor of interferon α/β induction.. Ryan. 5638–5648 (2002). G. TGF-β. Weis. such as ManLAM. and further investigations into the function of the mouse homologues of DC-SIGN33. Kadowaki. I. E. & Adema. et al. 71–81 (2000). 167. & Lanzavecchia. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells.. C. A mouse homologue of DC-SIGN functions in vivo as a pathogen receptor for blood-borne antigens141. J. & Steinman. & Ozinsky. 85. Med. 24. Exp. & Angman. Pathol. A. Colonna. J. B. Gordon. et al. 231–237 (1998). G. I. W. 14. Science 291. Molecular cloning and expression of cDNA encoding human macrophage C-type lectin. J. 3. 6. 162. G. 194. The dendritic cell receptor for endocytosis. Innate immune recognition. J.. C. 5767–5774 (2001). VOLUME 3 | SEPTEMBER 2003 | 7 0 7 © 2003 Nature Publishing Group . 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. Thoma-Uszynski. Y. as well as with other pathogens. Opin. Turley. 103–110 (2002). Taylor. J. Sallusto. a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Underhill. a novel C-type lectin specific to Langerhans cells. A. Banchereau. and how they shift the balance between TLR and C-type-lectin signalling. opens up a new area of research into how different subsets of DCs in vitro or in vivo that express different sets of C-type-lectin receptors and TLRs recognize and handle different pathogens. 245–252 (1998). et al. J. DEC-205. induce their immunosuppressive effect on DCs. 9. A. J. Nature Rev. Figdor. 25. It is probable that the expression of various C-type lectins by DC subsets has evolved to capture a range of different antigens. Sallusto.

Chem. T. J. Virol. Kupfer. I. Exp. et al. Van Die. D. Lowe. 115–123 (2003). T. Granelli-Piperno.. This paper shows the mechanism by which mycobacteria escape immune surveillance by modulating TLR signalling through targeting DC-SIGN. 545–554 (2002). 71. Cell 97. Apostolopoulos. Nature Biotechnol. Higashi. 84. 60. Immunity 16. Frison. A. Immunol. M. T. 65. Navarro-Sanchez. 76. Chem. et al.. Linehan. S. 20. J. Drickamer. Porrot. Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. J. M. C. Scharnowske. Med. This paper identifies DC-SIGN as a target for Mycobacterium tuberculosis. L. P. Finkel.. K. Moris. R. A. Pohlmann. Immunol. 3. 471–478 (2003). 35. & van Kooyk. E. Sci.. W. Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. J. 389–398 (1994). T. S. 78. Geijtenbeek. M. Identification of different binding sites in the dendritic cell-specific receptor DC-SIGN for intercellular adhesion molecule 3 and HIV-1. Mitchell.. J. T. 12855–12865 (2002). et al. S. Okano. 75. is a receptor for Leishmania amastigotes. T. 903–910 (2002). Subset of DC-SIGN+ dendritic cells in human blood transmits HIV-1 to T lymphocytes. R. 54. E. S. & Feizi. 69. R. O. 20358–20366 (2003). Stambach. & Schwartz. Puig-Kroger.. www. D. Macrophage-tropic HIV induces and exploits dendritic cell chemotaxis. 6841–6844 (2002). 76. and murine dc-sign. B. Cell 111. Geijtenbeek. The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Mitchell. A. 33. Immunol. & McKenzie. R. Lin. Biol. et al. 8356–8360 (1992). 2733–2737 (1998). B. & van Kooyk. Curr. Nef-induced CD4 degradation: a diacidicbased motif in Nef functions as a lysosomal targeting signal through the binding of β-COP in endosomes. M. B. Cell 100. H. Virol. Natl Acad. Int. J. J. while mature cells efficiently transmit both M. M. This paper shows that in vivo targeting of C-type lectin receptors might lead to tolerance induction. Med. 12. 170. Baribaud. P. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. Med. 6712–6717 (1999). & Littman. Appelmelk. 75. A. K. A. Baribaud. Chem. Opin. 76. Fukui. Vaccine 18. U. Hawiger. W.. Cambi.. 68. Hendrickson. B.and T-tropic virus to T cells. Finkel. 277. Avrameas. 76. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. C. et al.. 49. 44. J. R.. M. L. de Fougerolles. et al. Med. & Rivas. USA 89. N. et al. 22. Immunol. Three-dimensional segregation of supramolecular activation clusters in T cells.. a C-type lectin of Langerhans cells. 45. & Steinman. 40. et al. 143–151 (2003). 33. 769–779 (2001). 86. Exp. Med.. 46. Geijtenbeek. 204. Eur. Structural study of N-linked oligosaccharides of human intercellular adhesion molecule-3 (CD50). Lawson. J. Weis. Diamond. Baribaud. et al. 197. et al. Virol.. Immunol. O. et al. J. & Steinman. T. J. J. EMBO rep. Piguet. Tailleux. Chem. Chem. Immunity 17. 75. Eur. Virol. P. Curr. 401–410 (2003). 30335–30336 (1999). Re-evaluation of monosaccharide binding property of recombinant soluble carbohydrate recognition domain of the natural killer cell receptor NKR-P1A. et al. Bonifaz. L. 11314–11320 (2002). V. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. 38. J. M. Virol. 72. Sciaky. 25. 532–538 (2003). A.. & Chai.. V. Cutting edge: carbohydrate profiling identifies new pathogens that interact with dendritic cellspecific ICAM-3-grabbing nonintegrin on dendritic cells. J. Int. W. Apostolopoulos. Y. Pietersz.. J.. Montero.. A. 276. Oligosaccharide microarrays for high-throughput detection and specificity assignments of carbohydrate–protein interactions. L. Natl Acad. Engering. G. Ligand-specificity of the selectins. Engering. Immune escape through C-type lectins on dendritic cells. 36766–36769 (2002). 1–6 (2003). N.. 274. Biol. 97. Lee. Rev. MartinezPomares. Lawson. U. J. rhesus macaque.. N. 1866–1875 (2002). 4070–4080 (2003). Binding properties of the mannose receptor. 43.. W. et al. Sci. L. a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Science 285. Delgado. M. Virology 305. Taylor. Satoskar. B. 283–294 (2000). Daniels. Targets 6. 3174–3184 (2000). Chem. 1011–1017 (2002).. Blood 100. W. et al. & Watson. & Drickamer. F. 4. DC-SIGN: a guide to some mysteries of dendritic cells. J. Biol. A. Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells. C. 79.. R. Nature Immunol. This paper describes the mechanism of carbohydrate recognition by DC-SIGN. 63. I. Exp. 162. Inhibition of human immunodeficiency virus type 1 Envmediated fusion by DC-SIGN. 927–930 (2002). C. Analysis of mannose binding by sitedirected mutagenesis and NMR. | SEPTEMBER 2003 | VOLUME 3 76. E. Pattern recognition receptors: doubling up for the innate immune response. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. S. 32. Glycobiology 13. 37. 197. Alvarez.. HIV-1 Nef-induced upregulation of DC-SIGN in dendritic cells promotes lymphocyte clustering and viral spread. J. The dendritic cell specific C-type lectin DC-SIGN is a receptor for Schistosoma mansoni egg antigens and recognizes the glycan antigen Lewis-x. M. K. Biol. J.. Sol-Foulon. The role of DCSIGN and DC-SIGNR in HIV and Ebola virus infection: can potential therapeutics block virus transmission and dissemination? Expert Opin. A. Eur. Science 257. A. The macrophage C-type lectin specific for galactose/N-acetylgalactosamine is an endocytic receptor expressed on monocyte-derived immature dendritic cells. Trimeric structure of a C-type mannose-binding protein. M. 87. DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. D. Chem. 56. B. 186. B. W. 42. Biochem. L. 51. J. C. Immunobiol. Glycosylation in the control of selectin counterreceptor structure and function. 527–535 (2001). J. Heterogenous glycosylation of ICAM-3 and lack of interaction with Mac-1 and p150. 48. Struct. 47–56 (2002).. Addition of a single gp120 glycan confers increased binding to dendritic cell-specific ICAM-3-grabbing nonintegrin and neutralization escape to human immunodeficiency virus type 1. 269. 73. Feizi. Jr. et al. Cell. 36. G. 71. Human cytomegalovirus binding to DC-SIGN is required for dendritic cell infection and target cell transinfection. 221–227 (1999). 21–29 (1999). 197. 192. F. USA 100. 5. 70. Paxton. Gordon. K. 5313–5323 (2003). C.. S. D. Expression of a mannose/fucose membrane lectin on human dendritic cells. 98. The first paper to identify that internalization of HIV-1 is required for the infection of T cells by DCs. 278. Exp. Kammerer. N. & Taylor. B.. Virol. 9. Sweet ‘n’ sour: the impact of differential glycosylation on T cell responses. A. M. Y. P. 82–86 (1998). S. R. 12028–12038 (2001). A. 63–73 (1999). Ex vivo targeting of the macrophage mannose receptor generates anti-tumor CTL responses. D. Y. F. 277. 47. Binding of sugar ligands to Ca2+-dependent animal lectins. Pohlmann. R. Biol. Van Vliet. L. Subunit organization and binding to multivalent ligands. et al. L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. M. Engering. This paper identifies the carbohydrate specificity of DC-SIGN and the identification of large variety of pathogens that interact with DC-SIGN. J. Pietersz. J. 30. Nishizaki. 74. J. A hypothesis of the innate immune function of pattern recognition receptors expressed by DCs and macrophages is presented in this paper. van Kooyk. K. Am. a C-type surface lectin in human DCs. et al. et al. 26. et al.. Exp. Monks.. 83. B. S. 28939–28945 (2001). J. 423–431 (2002). A. Granelli-Piperno. V. 643–646 (2001). T. Virol.nature.. S.. et al. A. M. 66. Signaling takes shape in the immune system. 145–155 (2002). E. 92. Y. Colmenares. Immunity 6.95. 15505–15511 (1994). 653–664 (2002). Dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN.. W. 52.. J. A. A. et al. et al. Immunol. F. W. 61. 91. 58. 277. 81. 10299–10306 (2002). 187–197 (1997). Immature dendritic cells selectively replicate macrophagetropic (M-tropic) human immunodeficiency virus type 1. Pope. Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques. A. Pathol. A. Wormald. J. et al. 4498–4503 (2003). Dustin. M. D. G. 491–494 (2000). 62. 72. J. Biol. Biol. 77. 1020–1029 (2001). 55. 95. Structure 2. 1227–1240 (1994).. E. Lozach. 41. J. M. A. 1780–1786 (2002). J. Grakoui. Science 294. te Velde. et al. A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Weis. Virol. L. Nobile. Higashi. 34. Cameron. 30. F. 1511–1519 (2000). A. a C-type lectin on dendritic cells that unveils many aspects of dendritic cell biology. The first paper that described the molecular mechanism by which DCs transmit HIV-1. Eur.. Barnes.. Biol. S. I. Bay. K. & Doms. Biol. 278. J.. 268. 89. J. 57. Biol. 64.. T. T. J. 39. & Kupfer. 196. 1627–1638 (2002). 82. V. pigtailed macaque. & Gordon. CD209). et al. 19–36 (2002). The cell surface receptor DC-SIGN discriminates between Mycobacterium species through selective recognition of the mannose caps on lipoarabinomannan. DC-SIGN. Halary. Trends Immunol. R. Glycobiology 13. 80. Immunol. Oligolysine-based oligosaccharide clusters: selective recognition and endocytosis by the mannose receptor and dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin. Immunity 16. et al. Trends Immunol. N. Increased expression of DC-SIGN+ IL-12+IL-18+ and CD83+IL-12–IL-18– dendritic cell populations in the colonic mucosa of patients with Crohn’s disease. Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. Curtis. S. Cis expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. J. Abe.. H. B. The immunological synapse: a molecular machine controlling T cell activation. D. W. 5513–5516 (2003). 23. Dendritic-cell-specific ICAM3grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. et al. Pello. J. I. 480–485 (2002). 887–896 (2003). et al. Biochem. I. 93. A.. 88. 383–387 (1992). Chem. Increasing diversity of animal lectin structures. Maeda. 394–400 (1996). Human macrophage lectin specific for galactose/N-acetylgalactosamine is a marker for cells at an intermediate stage in their differentiation from monocytes into macrophages. 50. N. 585–591 (1996). N. Gordon. F. 33. M. Corbi. I. I. A. Cell 100. Immunol. 90.REVIEWS 29. Drickamer. Prigozy. The mannose receptor delivers lipoglycan antigens to endosomes for presentation to T cells by CD1b molecules. A. J. A. 10281–10289 (2001). et al. & Weis. J. Iobst. V.. Geijtenbeek. Virol. A. S. Fadden. Geijtenbeek. Exp. & Jameson. 94. 587–597 (2000). B. Gardner. P. Mycobacteria target DC-SIGN to suppress dendritic cell function. Biol. 23922–23929 (2003). N. et al. 1635–1639 (2003). Leukoc. 2163–2166 (2001). DC-SIGN and DC-SIGNR: helping hands for HIV. A. 67. B. et al. Bitton. Doms. Kato. S. Freiberg. 77. 186. Immunol. Ther. et al. Functional and antigenic characterization of human. Geijtenbeek. Immunol. Galustian. Human immunodeficiency virus envelope (gp120) binding to DC-SIGN and primary dendritic cells is carbohydrate dependent but does not involve 2G12 or cyanovirin binding sites: implications for structural analyses of gp120–DC-SIGN binding. Immunol. Steinman. K. M. A. Eur. DC-SIGN-mediated internalization of HIV is required for trans-enhancement of T cell infection. Tassaneetrithep. Expression of multilectin receptors and comparative FITC-dextran uptake by human dendritic cells. 278. Funatsu. 121–127 (2003). J. Kogelberg. et al. 1714–1723 (2000). F. C.. Martinez-Pomares. Jameson. Eur. A. 31. and Chan. G.. Lue. J. et al. H. 135–144 (2002). 163. Vestweber. & Harn.. 59. J. Gregorio. & Springer. Chem. 77. et al. Characterization of carbohydrate recognition by langerin. Cell 78. DC-SIGN. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. Nature 395. Proc.. 14. Delgado. Hogquist. Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Kwon. Structural basis for selective recognition of oligosaccharides by DC-SIGN and DC-SIGNR. A. 85. Simmons. A. B. Dwek. Feinberg. S. Proc. Aldehyde-mannan antigen complexes target the MHC class I antigen-presentation pathway. & Geijtenbeek. A novel adhesion pathway that regulates dendritic cell trafficking and T cell interactions. Hong. J. Cell 103. B. S. et al. N. 612–616 (1995). Induction of TH2 responses and IgE is largely due to carbohydrates functioning as adjuvants on Schistosoma mansoni egg antigens. R.. Y. A. Med. 194. 61. & McKenzie. R. Rev. & Drickamer. Sol-Foulon. R. P. I. S. 823–829 (2003). & Drickamer. T. O. & Pohlmann. 7–17 (2003). & van Kooyk. 96. 1008–1012 (1995). A. N. H.com/reviews/immunol © 2003 Nature Publishing Group . 587–594 (2000). 708 53. DC-SIGN and L-SIGN are high–affinity binding receptors for hepatitis C virus glycoprotein E2. et al. A. C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans. et al. 921–931 (2002). 20686–20693 (2002). J. Biol.. T.

. Med. Clin.. 128. M... 75. & Kaufman. 101.. Brown. J. Nigou. Callebaut. 110. 106. & Fauci. This paper. This paper shows that potentially other C-type lectins are also involved in the capture of HIV-1-encoded envelope glycoprotein gp120.. Ugolini. Krust. AIDS Res. 100. Immunol. D. M. Jonuleit. 6883–6890 (2000). Targeting the function of mature dendritic cells by human cytomegalovirus: a multilayered viral defense strategy.. 299. R. D. 122.. Microbiol. Distribution and immunophenotype of DC-SIGN-expressing cells in SIVinfected and uninfected macaques. 121. J. Science 300. Q. 3623–3634 (1998). G. D. T. AIDS 16. 7812–7821 (2002). K. X. E. 76. 131. T. We thank A. and transmission. Syndecans serve as attachment receptors for human immunodeficiency virus type 1 on macrophages. & Enk. P. et al.. 2908–2916 (2002). M. N. 107. M. Virol. M. The role of DCSIGN and DC-SIGNR in HIV and SIV attachment. 11827–11836 (2002). Thurnher. D. et al. M. Pohlmann. 113. Immunol. 6. M. et al. J. Rhesus macaque and chimpanzee DC-SIGN act as HIV/SIV gp120 trans-receptors. 114. A. Grunebach. A fatal attraction: Mycobacterium tuberculosis and HIV-1 target DC-SIGN to escape immune surveillance. & Geijtenbeek. S. Nisole. et al. Vercellone. Marginal zone macrophages express a murine homologue of DC-SIGN that captures blood-borne antigens in vivo. A. Microbiol. & Underhill. Rollinghoff. A. Dectin-1 mediates the biological effects of β-glucans. New structural insights into the molecular deciphering of mycobacterial lipoglycan binding to C-type lectins: lipoarabinomannan glycoform characterization and quantification by capillary electrophoresis at the subnanomole level. Capture and transfer of simian immunodeficiency virus by macaque dendritic cells is enhanced by DC-SIGN. 997–1009 (2001). A. 1–5 (2003). I. 2936–2951 (2002).. R. J. Sada. A. 71. S. C. T. Simian immunodeficiency virus dramatically alters expression of homeostatic chemokines and dendritic cell markers during infection in vivo. Ehlers. J. G. This report shows that other non-C-type lectins can function similarly to DC-SIGN as a trans-receptor for HIV-1. J. Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan with profound physiological effects. 975–983 (2002). Immunol. 105. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette–Guerin: involvement of toll-like receptors. N. Granucci. 142. T. Hum. 108. & Reinhart. Virol.. D. Herndier. L. B. 120. & Stenger.. F. S. E. G. Geijtenbeek. 76. N. 6710–6713 (2001). M. Syndecan captures. J. T. M.. Hockey. Y. 13.. S. et al. & Doms. Murphey-Corb. Nguyen. Sanders.. 140. G. 445–457 (2002). 36–37 (2001). M. H. J. Turville. J. Diversity of receptors binding HIV on dendritic cell subsets. 4070–4079 (1994). G. protects. 2. R. Mengozzi. Turville. & Kaisho. G. Mol. similar to human DC-SIGN. 112. M. Immune recognition. A. S. 9187–9200 (2001). B. 3. 102. Schmitt. 166. Binding of the terminal mannosyl units of lipoarabinomannan from a virulent strain of Mycobacterium tuberculosis to human macrophages. & Hildreth. & Lackner. R. W. Med. van Vliet for critical reading of the manuscript. Knop. Yu Kimata. A. J. Herrera. Y. M. Tsuji. Jiao.. & Puzo. 1353–1362 (2000). 167–174 (1993). 358–367 (1997). 129.. 7477–7485 (2001). van Kooyk. 141. Virology 281. T. Exp. et al. Hematol. 153–159 (2003). J. Virol. T. 27–39 (2003). B. H. & Hovanessian.gov/LocusLink/ BDCA2 | CCR5 | CD205 | CD206 | CD207 | CD209 | CD4 | CLEC1 | DCAL1 | DCIR | dectin-1 | GM-CSF | gp120 | ICAM2 | ICAM3 | IFN-γ | IL-4 | IL-10 | IL-12 | LFA1 | Nef | TLR2 | TLR4 | TLR6 | TLR7 | TLR9 FURTHER INFORMATION Consortium for functional glycomics: http://web.. & Daffe. B. J. Akira. et al. including our collaborators whose work has helped shape the ideas. Hull. S. 10523–10526 (2001). Molecular and functional characterization of human Dectin-1. J. shows that C-type lectins can modulate TLR signalling. Rev. Immunol. NATURE REVIEWS | IMMUNOLOGY 132. infection. Nature Immunol. Glycobiology 8.. 115. Online links DATABASES The following terms in this article are linked online to: LocusLink: http://www. 109. J.. E. Canavera. Productive infection of plasmacytoid dendritic cells with human immunodeficiency virus type 1 is triggered by CD40 ligation. 197. G. J. B.. Alvarez. 1107–1117 (2003). Gilmour. 123. Rae. 675–680 (2001). Human immunodeficiency virus type 1 attachment to HeLa CD4+ cells is CD4 independent and gp120 dependent and requires cell surface heparans. nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. P. D. et al. liver organization and the Dutch Cancer Foundation for their financial support.nlm. Kaufmann. Takeda. Geijtenbeek. Schwartz. H. F. 111. Mondor. A. Exp.. Zhang. Exp. Kavanagh. Zelle-Rieser. Virol. 891–893 (2002). Andoniou. the AIDS foundation. Plasmacytoid dendritic cells are highly susceptible to human immunodeficiency virus type 1 infection and release infectious virus. Gilleron. C. Virol. McDonald.. Inhibition of HIV infection by the cytokine midkine.. M. 117. D. A. & Khoo. 2587–2590 (1990). R. & Gallay. 1295–1297 (2003). AIDS Res. Blood 98. 124. J. D. Choi. S. Schuler. & Schaible. VOLUME 3 | SEPTEMBER 2003 | 7 0 9 © 2003 Nature Publishing Group . 168. G. 1684–1691 (2003). C. S. K. 3. Evaluation of lipoarabinomannan for the serological diagnosis of tuberculosis. P. Mannosylated lipoarabinomannans inhibit IL-12 production by human dendritic cells: evidence for a negative signal delivered through the mannose receptor. U. 978–987 (2000). and transmits HIV to T lymphocytes. A. Raftery. Exp. the Dutch stomach. Virol.. Five mouse homologues of the human dendritic cell C-type lectin. A division of labor: DC subsets and HIV receptor diversity. 72. 137. 28. Z. 133. 483–493 (2003). J. et al. IL-10 converts human dendritic cells into macrophage-like cells with increased antibacterial activity against virulent Mycobacterium tuberculosis. Interactions between Mycobacterium tuberculosis and host cells: are mycobacterial sugars the key? Trends Microbiol.. B. 116. Trends Mol. J. G. N. E. 152. S. Larsson. Clin. W. J. M. Reichert. Gantner. & Sattentau. Immunol. D. J. We are grateful to the Netherlands Organization for Scientific Research. Nature Immunol. G. Fong. G. Cell-surface heparan sulfate proteoglycan mediates HIV-1 infection of T-cell lines.. Immunity 18. 76.. J. 127. Activation of HIV-1 specific CD4+ and CD8+ T cells by human dendritic cells: roles for crosspresentation and non-infectious HIV-1 virus. Patel. 136. 1077–1084 (2001). 1119–1124 (2003). 30. A. Pohlmann. Nature Immunol. D. Park. & Puzo. S. Andrews.. 10. Retroviruses 9. 1213–1222 (2000). Med. Immunol. D. & Engleman. 104. et al. M. & Gotch. Bobardt. A recent paper showing the intracellular rearrangement of HIV-1 towards the immunological synapse. J. 2. E. Immun. Hum.. et al. & Brossart. S. together with reference 138. Dendritic cells are host cells for mycobacteria in vivo that trigger innate and acquired immunity. 125. Soilleux. Collaborative induction of inflammatory responses by Dectin-1 and Toll-like receptor 2. C. Abbey. J. Weck. 135. W. P. S. et al. J. Frank. Eur. Infectious and whole inactivated simian immunodeficiency viruses interact similarly with primate dendritic cells (DCs): differential intracellular fate of virions in mature and immature DCs.mit. DC-SIGN interactions with human immunodeficiency virus: virus binding and transfer are dissociable functions. et al. 11033–11041 (2002). 197. 76. 165. S. M. E. DC-SIGN. I. Int. 75. J. Chatterjee. 33.. et al. & Gordon. 9. 2482–2488 (2001). Weissman. 119.. Recruitment of HIV and its receptors to dendritic cell–T cell junctions.. & Bhardwaj. Nigou.nih. B. J. Bobardt. E. RicciardiCastagnoli. 103. Appelmelk.REVIEWS 99. M. 1283–1290 (2001)..edu/glycomics/consortium Access to this interactive links box is free online. 134. Biol. 68.. Role of dendritic cells in immunopathogenesis of human immunodeficiency virus infection. K. F. 138. Patterson. J. C. 126. S. 1309–1315 (2002). HIV gp120 receptors on human dendritic cells. J. Med. 1294–1301 (2002). Virol.ncbi. S.. Blood 100. S. J. Akira. J. 328–335 (1998). Involvement of macrophage mannose receptor in the binding and transmission of HIV by macrophages. Differential transmission of human immunodeficiency virus type 1 by distinct subsets of effector dendritic cells. G. Immunity 15. Leukoc. D. Biol. Toll-like receptors: critical proteins linking innate and acquired immunity. 130. G. Retroviruses 18. Simmons. Acknowledgements We thank all former and present members of our group. 139. F. Induction of interleukin 10-producing. David. Blood 101. Infection of dendritic cells by murine cytomegalovirus induces functional paralysis. Baribaud. A dangerous liaison between two major killers: Mycobacterium tuberculosis and HIV target dendritic cells through DC-SIGN. J. X. 248–264 (2001). L. et al. Fortsch. Virology 286. Engering and S. 1–6 (2001). A. Briand. & Degli-Esposti. H. et al. Nature Immunol. 79. M. Saphire. 118. B. G. Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. et al. 101–107 (2001). 192. Nature 413. kidney. Brown. M. M. & Torres. Brennan. et al. Schlesinger. Exp. S. M. J. 113–120 (1998).. Fallert. A. 197. A new receptor for β-glucans. Immunol. Med. T. 1319–1329 (2002). 75. P. Lett. Virol. A. J.. 1021–1029 (2002). Infect.

.

or email articles for individual use. However. .Copyright of Nature Reviews Immunology is the property of Nature Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. users may print. download.