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DC-SIGN

DC-SIGN, also known as CD209 (cluster of differentiation 209), is a C-type lectin receptor that functions as a pathogen-recognition molecule and adhesion protein primarily expressed on the surface of immature dendritic cells and macrophages.^[1] This type II transmembrane glycoprotein, with a molecular weight of approximately 44 kDa, features a cytoplasmic tail, a transmembrane domain, a neck region with tandem repeats, and a C-terminal carbohydrate-recognition domain (CRD) that binds high-mannose and fucose-containing glycans on microbial surfaces.^[2] Encoded by the CD209 gene on chromosome 19p13.2, DC-SIGN was first identified in 2000 as a dendritic cell-specific receptor capable of binding HIV-1 envelope glycoprotein gp120, facilitating viral capture and transmission to T cells.^[3] In the immune system, DC-SIGN plays a pivotal role in bridging innate and adaptive immunity by mediating the adhesion of dendritic cells to T lymphocytes via interaction with intercellular adhesion molecule-3 (ICAM-3), thereby promoting T-cell activation and synapse formation.^[1] It also enables the endocytosis and internalization of pathogens, such as HIV-1, Ebola virus, Dengue virus, Mycobacterium tuberculosis, and SARS-CoV-2, allowing for antigen processing and presentation while modulating cytokine production, including IL-10, to regulate immune responses.^[2] Expression is highest in lymphoid tissues like lymph nodes and spleen, as well as in placental and endothelial cells, with lower levels in monocytes and subsets of B cells.^[1] Genetic variations in CD209, such as the promoter polymorphism rs4804803 (-336A/G), have been associated with altered susceptibility to infectious diseases; for instance, the G allele confers protection against severe Dengue but increases risk for HIV-1 acquisition and tuberculosis.^[2] Beyond infections, DC-SIGN contributes to autoimmune and inflammatory conditions by influencing dendritic cell maturation and tolerance induction.^[4] Its dual role as both an immune enhancer and a potential exploiter by pathogens underscores its significance in host-pathogen interactions.^[5]

Discovery and Nomenclature

Initial Identification

DC-SIGN was first identified in 2000 by Teunis B.H. Geijtenbeek and colleagues as a novel dendritic cell-specific receptor for intercellular adhesion molecule 3 (ICAM-3). Using expression cloning in COS-1 cells transfected with a monocyte-derived dendritic cell (MDDC) cDNA library, the researchers employed a flow cytometric adhesion assay with ICAM-3-Fc-coated beads to isolate clones that specifically bound ICAM-3, revealing a type II transmembrane protein distinct from known integrin receptors like LFA-1 and αDβ2.^[6] The protein was initially characterized as a 44 kDa C-type lectin based on immunoprecipitation from surface-labeled MDDCs and SDS-PAGE analysis, which showed a single band at this molecular weight under reducing conditions. Functional assays demonstrated that DC-SIGN mediates high-affinity binding to ICAM-3 expressed on resting T cells (IC50 = 7 μg/ml), facilitating transient DC-T cell adhesion and clustering of the T cell receptor at the immune synapse interface. Blocking DC-SIGN with monoclonal antibodies inhibited DC-induced proliferation of allogeneic T cells by more than 60%, underscoring its role in initiating primary immune responses.^[6] To emphasize its specificity and non-integrin nature, the researchers named the receptor Dendritic Cell-Specific ICAM-3-Grabbing Non-integrin (DC-SIGN), highlighting its exclusive expression on dendritic cells and function in "grabbing" ICAM-3 to support immune cell clustering without relying on integrin-mediated adhesion. This discovery distinguished DC-SIGN from other ICAM-3 receptors and established it as a key player in early T cell activation.^[6]

Gene Designation

The CD209 gene, encoding the DC-SIGN protein, was cloned in 2000 through expression cloning from a human dendritic cell cDNA library, identifying it as a novel C-type lectin receptor specific to dendritic cells that binds ICAM-3 with high affinity.^[6] This cloning effort revealed the full-length sequence and confirmed its role in immune cell adhesion, building on an earlier isolation of its sequence from a placenta cDNA library in 1992 as an HIV-1 gp120-binding protein.^[7] The gene maps to chromosome 19p13.2, within a clustered genomic region spanning approximately 26 kb that includes related genes such as CD209L and CD23.^[8] Officially designated as CD209 by the HUGO Gene Nomenclature Committee, it carries aliases including DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) and CLEC4L (C-type lectin domain family 4 member L), reflecting its lectin properties and functional nomenclature.^[9] The CD209 gene consists of 7 exons, with the carbohydrate recognition domain (CRD) encoded across three separate exons, producing a primary transcript that yields a 404-amino acid type II transmembrane protein.^[8] The encoded protein features an N-terminal cytoplasmic domain, a transmembrane region, a neck domain with tandem repeats for structural flexibility, and a C-terminal CRD for carbohydrate binding.^[10] Early sequence analysis of CD209 demonstrated high conservation with other C-type lectins, particularly in the CRD, sharing structural motifs with macrophage mannose receptor and sharing approximately 77% identity with related family members like DC-SIGNR, underscoring its evolutionary ties to pathogen-recognition receptors.^[8]

Structure and Expression

Protein Structure

DC-SIGN is a type II transmembrane glycoprotein belonging to the C-type lectin family, characterized by a short N-terminal cytoplasmic tail of approximately 35 amino acids that contains dileucine and tyrosine-based motifs essential for receptor internalization and signaling.^[11] This tail is followed by a single transmembrane domain and an extracellular domain. The extracellular region includes a neck domain with seven tandem repeats of approximately 23 amino acids each that promotes oligomerization and a C-terminal carbohydrate recognition domain (CRD) of about 150 amino acids responsible for ligand binding.^[12] ^[13] The CRD of DC-SIGN features a typical long-form C-type lectin fold with two α-helical regions and a calcium-binding site critical for carbohydrate recognition.^[14] Binding to mannose-type glycans, such as those found in high-mannose oligosaccharides, is calcium-dependent and mediated by the conserved Glu-Pro-Asn (EPN) motif, which coordinates the sugar's C3 and C4 hydroxyl groups.^[14] The crystal structure of the DC-SIGN CRD, resolved at 1.6 Å resolution in complex with a biantennary glycopeptide, reveals a monomeric unit but highlights how the domain's flexibility allows adaptation to diverse glycan conformations. Recent structural analyses have identified a cryptic allosteric pocket in the CRD that allosterically modulates oligosaccharide binding (as of 2025).^[14] ^[15] Although the isolated CRD is monomeric, the full-length protein assembles into a homotetrameric structure, as evidenced by structural models integrating the neck region.^[16] The neck region of DC-SIGN contains potential N-linked glycosylation sites, including at Asn80, which bear complex-type glycans that shield the protein from degradation and enhance thermodynamic stability by reducing aggregation propensity.^[17] ^[18] These N-glycans, primarily located on the repeats, also influence ligand specificity by modulating the accessibility of the CRD and contributing to the overall glycan-binding avidity through steric and electrostatic effects.^[18] Oligomerization is driven by the neck domain's seven heptad repeats, which form a segmented α-helical coiled-coil structure that positions the four CRDs in a flexible, icosahedral-like arrangement approximately 13 nm from the membrane, enabling multivalent interactions essential for high-avidity binding to glycans.^[16] This tetrameric configuration is stabilized by hydrophobic interactions within the neck, with variations in repeat length across species or isoforms affecting the geometry and ligand presentation.^[19]

Cellular Expression

DC-SIGN, encoded by the CD209 gene, is primarily expressed on immature myeloid dendritic cells (DCs) and monocyte-derived DCs.^[20] Expression is also observed on alternatively activated macrophages, particularly the M2 subtype, which are induced by Th2 cytokines such as IL-4. In contrast, DC-SIGN levels are low or absent on mature DCs, where it is downregulated during DC maturation to shift focus from antigen capture to presentation.^[21] Tissue distribution of DC-SIGN is concentrated in sites of immune surveillance, with high expression on immature DCs in the dermis of the skin, mucosal surfaces such as the intestine and genital tract, and lymphoid organs including lymph nodes and spleen.^[21] Specialized macrophages expressing DC-SIGN are prominent in the placenta and lung, while the related receptor L-SIGN (also known as DC-SIGNR) is found on endothelial cells in the lung and placental capillaries.^[20] ^[21] DC-SIGN expression is upregulated during monocyte differentiation into DCs, driven by cytokines including IL-4 and GM-CSF, which promote the acquisition of DC-specific markers.^[20] This process enhances surface presentation on immature DCs for efficient pathogen recognition. Additionally, DC-SIGN exists in both surface and intracellular pools, with internalized receptors trafficking through recycling endosomes; upon cellular activation, these endosomal pools enable rapid mobilization back to the cell surface, facilitating dynamic ligand interactions.^[21] ^[22]

Physiological Roles

Adhesion and Immune Cell Interactions

DC-SIGN plays a pivotal role in mediating initial adhesion between dendritic cells (DCs) and naive T cells through its high-affinity binding to intercellular adhesion molecule-3 (ICAM-3) expressed on T cells. This interaction facilitates the formation of transient DC-T cell clusters, which are essential for stabilizing the immunological synapse and enabling effective scanning of the DC surface by T cell receptors prior to antigen recognition. Blocking DC-SIGN with specific antibodies significantly reduces this clustering, underscoring its necessity for early immune cell contact. Expressed primarily on DCs, DC-SIGN supports these adhesion events without requiring DC maturation, allowing immature DCs to engage multiple naive T cells efficiently.^[23] In addition to T cell interactions, DC-SIGN contributes to DC trafficking by binding ICAM-2 on endothelial cells, promoting tethering, rolling, and transmigration across both resting and activated endothelium under physiological shear stress conditions. This adhesion is calcium-dependent and distinct from integrin-mediated mechanisms, enabling DCs to migrate from peripheral tissues to lymphoid organs. The DC-SIGN-ICAM-2 interaction resists fluid shear forces better than DC-SIGN-ICAM-3 binding, facilitating efficient endothelial crossing during immune surveillance. Upon ligand engagement, DC-SIGN transduces intracellular signals through its cytoplasmic tail, which contains motifs such as a dileucine (LL) sequence for clathrin-mediated internalization and an ITAM-like tyrosine-based motif for downstream activation. These motifs recruit signaling molecules like Src family kinases (Lyn and Syk), leading to phosphorylation of ERK1/2 and activation of Raf-1 kinase. Raf-1 activation results in NF-κB acetylation, promoting anti-inflammatory IL-10 production by DCs while modulating Toll-like receptor responses. Sustained DC-SIGN-mediated adhesion enhances T cell activation by prolonging DC-T cell contacts, which fosters CD40-CD40L signaling and promotes IL-12 secretion from DCs, thereby influencing Th1/Th2 polarization toward protective immunity.^[23] In the context of co-stimulation with TLR ligands, DC-SIGN supports IL-12-dependent Th1 responses, while its signaling can bias toward Th2 in certain microenvironments by elevating IL-10.^[23] This dual regulatory capacity ensures balanced T helper differentiation during primary immune responses.

Antigen Capture and Presentation

DC-SIGN functions as an endocytic receptor on dendritic cells, facilitating the capture and internalization of glycan-bearing antigens through its carbohydrate recognition domain. Upon binding to mannose-containing structures on antigens, DC-SIGN mediates uptake via clathrin-coated pits, a process dependent on cholesterol-rich membrane domains and dynamin, as well as specific cytoplasmic motifs such as the di-leucine (LL) and tri-acidic (EEE) sequences.^[4] This internalization directs antigens to late endosomal and MHC class II compartments (MIIC), where they undergo proteolytic processing for loading onto MHC class II molecules, enabling presentation to CD4+ T cells.^[24] In addition to conventional MHC class II presentation, DC-SIGN supports cross-presentation of exogenous antigens on MHC class I molecules, crucial for priming CD8+ T cells. Targeting the neck region of DC-SIGN prolongs antigen residence in early endosomes, delaying lysosomal degradation and promoting translocation to the cytosol via the endosome-to-cytosol pathway, where antigens are degraded by the proteasome and loaded onto MHC class I through TAP transport.^[25] In contrast, engagement of the carbohydrate recognition domain routes antigens more rapidly to lysosomes, favoring degradation over cross-presentation. This selective routing enhances the efficiency of cytotoxic T cell responses against extracellular threats.^[26] DC-SIGN also contributes to humoral immunity by collaborating with other C-type lectins to deliver antigens that promote B cell activation and differentiation. Antigen targeting to DC-SIGN-expressing antigen-presenting cells induces robust antibody responses, including IgG subclasses, through the promotion of T follicular helper cell differentiation and germinal center formation in B cells, as demonstrated in mouse models.^[27] Signaling through DC-SIGN modulates antigen processing and the immune milieu via the Raf-1/MEK/ERK pathway. Ligand binding activates Raf-1 phosphorylation by kinases like PAK and Src family members, leading to MEK/ERK activation without full engagement of the canonical MAPK cascade. This pathway influences processing efficiency by altering endosomal trafficking and enhances anti-inflammatory cytokine production, such as IL-10, via NF-κB p65 modification, thereby fine-tuning the cytokine environment for balanced immune responses.^[28]

Pathogen Recognition and Infections

Viral Interactions

DC-SIGN plays a critical role in HIV-1 infection by binding to the high-mannose glycans on the envelope glycoprotein gp120, facilitating viral capture by dendritic cells (DCs).^[29] This interaction enables both cis-infection of DCs and trans-infection of CD4+ T cells, where DCs act as reservoirs to transfer intact virions to T cells in lymphoid tissues, enhancing viral dissemination.00052-7) Upon binding, DC-SIGN mediates rapid internalization of HIV-1 into a non-degradative, low-pH compartment, preserving viral infectivity without lysosomal fusion and allowing prolonged storage in DC reservoirs.^[30] Additionally, gp120-DC-SIGN engagement induces IL-10 production in DCs, which delays antiviral responses by suppressing pro-inflammatory cytokines and impairing T cell activation. In Ebola virus infection, DC-SIGN interacts with the heavily glycosylated envelope glycoprotein (GP), promoting viral attachment and entry into DCs, though it serves primarily as an attachment factor rather than a full entry receptor.^[31] This binding facilitates DC infection, leading to impaired DC maturation and suppression of type I interferon (IFN) production, which contributes to immune evasion and systemic viral spread.^[32] Studies have identified multivalent mannose-functionalized fullerene derivatives as potent inhibitors of this GP-DC-SIGN interaction, blocking Ebola pseudovirus infection in cell models with subnanomolar IC50 values in 2015 research. DC-SIGN binds the S1 subunit of the SARS-CoV-2 spike protein via its carbohydrate recognition domain (CRD), enhancing viral entry into DCs and promoting trans-infection of permissive cells such as ACE2-expressing lung epithelial cells.^[33] L-SIGN, a related receptor, cooperates in this process, with both lectins recognizing N-linked glycans on the spike to facilitate viral capture and dissemination.^[34] Research from 2021 to 2024 confirms this mechanism across variants, showing that glycomimetic antagonists selectively inhibit DC-SIGN-mediated trans-infection while sparing L-SIGN interactions, highlighting potential for targeted antiviral strategies.^[35]^[36] DC-SIGN also interacts with other viruses, including hepatitis C virus (HCV) via the E2 glycoprotein, enabling DC capture and trans-infection of hepatocytes to establish persistent infection.^[37] For dengue virus, binding to glycans on the precursor membrane (prM) protein of immature virions promotes DC infection and immune modulation, contributing to viral evasion.^[38] In Middle East respiratory syndrome coronavirus (MERS-CoV), DC-SIGN mediates trans-infection of target cells from DCs, as demonstrated in 2023 studies, underscoring its role in coronaviral pathogenesis.^[39] These interactions often induce IL-10 in DCs, delaying type I IFN responses and facilitating viral persistence across multiple pathogens.

Bacterial and Other Pathogen Interactions

DC-SIGN, a C-type lectin receptor, plays a key role in recognizing glycan structures on bacterial pathogens, facilitating their uptake by dendritic cells (DCs) while often modulating immune responses to favor pathogen persistence. For instance, in Mycobacterium tuberculosis, DC-SIGN binds specifically to the mannose caps on mannosylated lipoarabinomannan (ManLAM), a major cell wall glycolipid, enabling bacterial entry into DCs via receptor-mediated endocytosis. This interaction promotes phagocytosis but also triggers the secretion of anti-inflammatory interleukin-10 (IL-10), which suppresses pro-inflammatory cytokine production and impairs DC maturation, thereby aiding mycobacterial survival within host cells.^[40]^[41] Recent structural studies have elucidated DC-SIGN's interaction with Gram-negative bacteria, such as Escherichia coli. The receptor's carbohydrate recognition domain (CRD) binds to the R1-type core lipooligosaccharide (LOS) on E. coli, primarily through the outer core pentasaccharide, which acts as a multivalent crosslinker between DC-SIGN tetramers. This binding facilitates bacterial uptake by DCs, with fluorescence microscopy confirming strong adhesion to E. coli cells, potentially leading to immune activation via downstream signaling, though the exact immunomodulatory outcomes remain under investigation.^[42] Among parasites, DC-SIGN mediates interactions that influence infection dynamics and host cell transmigration. In Leishmania amazonensis infections, DC-SIGN on DCs facilitates direct contact with neutrophils, promoting DC maturation and parasite elimination through enhanced tumor necrosis factor-alpha (TNF-α) and reactive oxygen species (ROS) production; neutralization of DC-SIGN increases parasite burden and impairs this protective response. For Schistosoma mansoni, DC-SIGN recognizes Lewis X (LeX)-containing glycans on schistosomula-derived extracellular vesicles (EVs), driving their internalization by monocyte-derived DCs and inducing both pro- and anti-inflammatory cytokines like IL-12 and IL-10, which contribute to immune evasion by modulating DC activation.^[43]^[44] Fungal pathogens exploit DC-SIGN for endocytosis via mannan recognition, exemplified by Candida albicans. DC-SIGN specifically binds N-linked mannans on the fungal cell wall, enabling phagocytosis by DCs, as demonstrated by reduced uptake of glycosylation mutants lacking these structures; this process influences cytokine profiles, such as IL-6 production, highlighting DC-SIGN's role in antifungal immunity. Overall, many bacterial, parasitic, and fungal pathogens present glycans that mimic host ligands, allowing DC-SIGN engagement to subvert Toll-like receptor (TLR) signaling and dampen effective immune responses.^[45]^[28]

Gene Family and Regulation

Evolutionary Family

DC-SIGN, encoded by the CD209 gene, belongs to the group II C-type lectin receptors (CLRs), a subgroup of the C-type lectin superfamily characterized by type II transmembrane topology and calcium-dependent carbohydrate recognition domains that facilitate pathogen sensing and cell adhesion.^[46] Within this group, DC-SIGN is part of the SIGN lectin subfamily, which includes closely related members such as human L-SIGN (CD209L), primarily expressed on endothelial cells in the liver and lymph nodes.^[47] These paralogues share high structural similarity, particularly in their C-type lectin domains, enabling functional redundancy in binding glycosylated pathogens, though they differ in tissue-specific expression patterns.^[48] In humans, the SIGN family arose through gene duplications from an ancestral CLR, with phylogenetic analyses indicating a first duplication event approximately 40 million years ago in the common ancestor of anthropoid primates, producing CD209L2 (retained in non-human primates but lost in humans) and an intermediate precursor.^[48] A subsequent duplication in the Old World primate lineage yielded the modern CD209 (DC-SIGN) and CD209L (L-SIGN), reflecting primate-specific adaptations that enhanced pathogen recognition under selective pressure from diverse microbial threats.^[49] Evidence of purifying selection (e.g., K_A/K_S ratios around 0.43-0.52) across these genes underscores their conservation for core functions in innate immunity, while sites under positive selection in L-SIGN suggest specialized roles in primate evolution.^[48] In contrast, rodents exhibit a marked expansion of the SIGN family, with mice possessing eight orthologous genes (SIGNR1 through SIGNR8) clustered on chromosome 8 adjacent to the CD23 locus, resulting from tandem duplications that likely occurred after the divergence of rodents from primates.^[50] This expansion has led to diversified ligand specificities among the murine paralogues; for instance, SIGNR1 closely mirrors human DC-SIGN in binding HIV glycoproteins, whereas others like SIGNR3 show functional orthology in host defense but reduced affinity for certain viral ligands.^[51] Such differences highlight species-specific evolutionary trajectories within the group II CLRs, adapting the family to distinct ecological and pathogenic pressures.^[52]

Transcriptional Regulation

The transcriptional regulation of DC-SIGN (CD209) is primarily governed by its promoter region, which spans approximately 236 base pairs from +251 to +487 relative to the transcription start site and contains critical binding sites for transcription factors such as NF-κB, Sp1, AP-1, and Ets-1.^[53] These elements mediate responsiveness to cytokines during dendritic cell (DC) differentiation; for instance, interleukin-4 (IL-4) upregulates DC-SIGN expression through activation of these sites, promoting its role as a marker of immature monocyte-derived DCs.^[54] In contrast, transforming growth factor-β (TGF-β) acts as a negative regulator, suppressing IL-4-induced DC-SIGN expression by interfering with differentiation signals.^[54] Epigenetic mechanisms further fine-tune DC-SIGN expression in a cell-type- and maturation-state-specific manner. During monocyte-to-immature DC differentiation, the CD209 promoter undergoes demethylation at key CpG sites (e.g., CpG2 from 63% to 0% and CpG3 from 100% to 20%), accompanied by gains in active histone marks such as H3K4me3 and H3K9 acetylation, which enhance transcription and support high expression in immature DCs. Conversely, repressive marks like H3K9me3 are lost, while in mature DCs and non-immune cells, increased DNA methylation at the promoter silences CD209, correlating with downregulation of the protein upon DC maturation.^[55] Post-transcriptional regulation involves microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). miR-155, upregulated during DC maturation in inflammatory contexts such as lipopolysaccharide stimulation, directly targets and suppresses CD209 mRNA, reducing DC-SIGN protein levels and thereby modulating pathogen binding and immune activation.^[56] Recent studies from the 2020s have identified lncRNAs influencing DC-SIGN stability and expression; for example, lncRNA MALAT1 promotes DC-SIGN production in DCs by enhancing IL-10 secretion and anti-inflammatory pathways, potentially stabilizing CD209 transcripts in tolerogenic contexts.^[57] Genetic variations in the CD209 promoter also impact expression levels and disease susceptibility. The -871A>G polymorphism (rs72486327) reduces promoter activity, leading to lower DC-SIGN expression, and has been associated with protection against tuberculosis by limiting Mycobacterium tuberculosis interactions with DCs.^[58] Similarly, the linked -336A>G variant (rs4804803) influences Sp1 binding and correlates with altered susceptibility to infectious diseases like tuberculosis.^[58]

Clinical and Therapeutic Implications

Disease Associations

DC-SIGN, encoded by the CD209 gene, exhibits associations with various non-infectious diseases and pathogen-related pathologies through its roles in immune modulation and cellular interactions. In cancer, particularly lung malignancies, DC-SIGN upregulation on tumor-associated macrophages (TAMs) drives metastatic progression. A 2025 study demonstrated that DC-SIGN mediates interactions between Gram-negative bacteria like Shigella sonnei and lung cancer tissues, binding to bacterial lipopolysaccharide (LPS) to promote M2 polarization of macrophages, enhanced lipid synthesis, and increased migration of cancer cells such as PC-9 and LLC lines. In vivo experiments in mouse models showed significantly larger tumor sizes, weights, and metastatic nodules in wild-type mice infected with bacteria compared to DC-SIGN (SIGNR1) knockout counterparts (P < 0.0001 for lung weight), highlighting DC-SIGN's mechanistic contribution to metastasis via immune evasion and tumor microenvironment remodeling.^[59] Furthermore, the morphology and distribution of DC-SIGN-positive dendritic cells in lymph nodes provide prognostic value in non-small cell lung cancer (NSCLC). Immunohistochemical analysis of resected lymph nodes from 34 NSCLC patients revealed that DC-SIGN-positive cells form mesh-like rosettes or clusters with complementary positioning to CD68-positive macrophages, and higher proportional areas of DC clusters correlated with better histological differentiation (P = 0.013) and improved overall survival (P = 0.059 overall; P = 0.007 in adenocarcinomas). Diminished DC presence and apoptotic macrophages in metastatic nodes further underscore DC-SIGN morphology as a potential biomarker for disease outcomes, independent of traditional staging.^[60] In autoimmunity and inflammatory conditions, DC-SIGN signaling contributes to immune tolerance by inducing interleukin-10 (IL-10) production in dendritic cells, which dampens proinflammatory responses and supports regulatory T cell development. This IL-10 induction occurs when DC-SIGN ligation coincides with Toll-like receptor or cytokine signals, promoting an anti-inflammatory milieu that may prevent excessive autoreactivity in diseases like rheumatoid arthritis (RA). Similar mechanisms are implicated in multiple sclerosis, where DC-SIGN antagonists are under investigation to restore immune balance.^[61] Genetic variants in CD209, notably the promoter polymorphism -96C>A, confer susceptibility to RA, with the A allele increasing risk (odds ratio 5.25; 95% CI 2.14–12.87; P < 0.0001) in Taiwanese cohorts through altered DC-SIGN expression on immune cells, though not directly linked to disease severity or treatment response. Haplotype analyses confirmed elevated frequencies of risk-associated alleles in RA patients (P = 0.004 for one haplotype), suggesting a role in early immune dysregulation.^[62] Post-viral complications involving DC-SIGN include heightened risk of type 2 diabetes (T2D) following COVID-19 infection. A 2025 proteome-wide Mendelian randomization analysis identified CD209 as a causal mediator between SARS-CoV-2 susceptibility and T2D onset, acting through persistent systemic inflammation that exacerbates insulin resistance and central obesity as cofactors. This pathway highlights DC-SIGN's potential in sustaining post-infection inflammatory states, with genetic proxies indicating targeted interventions could mitigate T2D progression in recovered patients.^[63] DC-SIGN family members also contribute to other pathologies, such as fibrosis and allergies. L-SIGN (CD209L), predominantly expressed on liver sinusoidal endothelial cells, influences hepatic fibrosis by modulating pathogen capture and endothelial barrier function, which in chronic settings promotes hepatic stellate cell activation and extracellular matrix deposition. In allergic diseases, DC-SIGN facilitates glycan-mediated uptake of allergens like house dust mite components by dendritic cells, driving Th2 polarization; however, allergens can downregulate DC-SIGN expression, altering DC maturation and function to impair tolerance and amplify IgE-mediated responses in conditions such as asthma.^[64]^[65]

Targeting Strategies

Targeting strategies for DC-SIGN primarily focus on modulating its function to combat infections, enhance vaccine efficacy, and regulate immune responses in inflammatory conditions. Inhibitors that block DC-SIGN binding have emerged as promising antivirals, particularly for pathogens exploiting this receptor for entry or dissemination. For instance, mannose-capped dendrimers, such as the polyvalent glycodendritic structure BH30sucMan, competitively inhibit DC-SIGN-mediated Ebola virus infection in cis and trans configurations with an IC50 in the nanomolar range, demonstrating efficacy in preclinical models. Similarly, glycofullerene oligomers functionalized with mannose residues exhibit multivalent binding to DC-SIGN, blocking HIV-1 attachment and infection by up to 90% in cell-based assays, with developments spanning 2015 to 2023 highlighting their biocompatibility and topological optimization for enhanced potency. These carbohydrate-based inhibitors leverage DC-SIGN's preference for mannose-containing glycans to prevent viral glycoprotein interactions without broad cytotoxicity. Recent advances include selective inhibitors distinguishing between DC-SIGN and its homolog L-SIGN (CD209L), both implicated in SARS-CoV-2 trans-infection. The small molecule Man84, a mannose derivative with a guanidinium group, binds L-SIGN with 50-fold selectivity over DC-SIGN (KD = 12.7 μM), while dimeric constructs like PM74 achieve nanomolar affinity (KD = 25 nM) and up to 1200-fold selectivity, inhibiting L-SIGN-dependent SARS-CoV-2 pseudovirus entry with an IC50 of 65 nM in 2024 studies. This differential targeting exploits a key amino acid difference (Asn385 in L-SIGN vs. Lys373 in DC-SIGN), offering potential for respiratory-focused therapies against SARS-CoV-2 and related viruses like Ebola. In vaccine development, DC-SIGN targeting facilitates targeted antigen delivery to dendritic cells, boosting CD8+ and CD4+ T-cell responses. Glycan-conjugated antigens, such as mannose- or Lewis Y-modified liposomes, enhance cross-presentation and elicit robust cytotoxic T-lymphocyte activity against HIV and cancer antigens in preclinical models, with up to 10-fold increases in IFN-γ-producing cells compared to non-targeted formulations. For cancer immunotherapy, multivalent glycan platforms route tumor-associated antigens via DC-SIGN to the endo-lysosomal pathway, promoting MHC class I/II presentation and antitumor immunity in mouse models. Ongoing dendritic cell-based vaccine trials, such as those for HIV, have incorporated or are exploring DC-SIGN ligands to amplify adaptive responses, building on phase I/II data showing improved T-cell proliferation. Anti-inflammatory strategies aim to disrupt DC-SIGN signaling to mitigate excessive immunosuppression in autoimmunity. Small molecules and glycomimetics that antagonize DC-SIGN reduce IL-10 secretion from tolerogenic dendritic cells, thereby enhancing pro-inflammatory cytokine production and T-cell activation in models of rheumatoid arthritis and inflammatory bowel disease. A 2024 review highlights how these agents, including sialylated mimics, interrupt the DC-SIGN/caveolin-1/NF-κB pathway, potentially restoring immune balance without broad immunosuppression. Preclinical evaluation of these therapeutics benefits from humanized models expressing human DC-SIGN (hDC-SIGN). In 2024, CRISPR/Cas9-engineered C57BL/6N mice knock-in with hDC-SIGN exhibited heightened SARS-CoV-2 susceptibility, with elevated viral loads in lungs and nasal turbinates post-intranasal challenge, enabling accurate testing of inhibitors like Man84 derivatives for efficacy and dosing. These models recapitulate human receptor-pathogen interactions, facilitating translation from bench to clinic.

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https://doi.org/10.4049/jimmunol.168.5.2118
[25]
Current Concepts of Antigen Cross-Presentation - Frontiers
Targeting DC-SIGN via its neck region leads to prolonged antigen residence in early endosomes, delayed lysosomal degradation, and cross-presentation. Blood ...
[26]
Mouse DC-SIGN/CD209a as Target for Antigen Delivery and ... - NIH
One of the most important functions of DC-SIGN is the induction of adaptive immunity. As such, the aim of this study is to determine the capability of mDC-SIGN ...
[27]
C-type lectin DC-SIGN: An adhesion, signalling and antigen-uptake ...
DC-SIGN was discovered by the observation that DCs bind the intercellular adhesion molecule (ICAM)-3 (CD50) with very high affinity. ICAM-3 is N-linked ...2. Dc-Sign Structure And... · 4. Various Ligands And... · 4.2. Signalling Through...
[28]
Human Immunodeficiency Virus Envelope (gp120) Binding to DC ...
DC-SIGN, a C-type lectin predominantly expressed on dendritic cells (DCs), can bind to the HIV envelope gp120 and transfer the virus to other permissive cell ...Gp120-Fc Binding Assay · Gp120 Binding To Dc-Sign And... · 2g12 And Cyanovirin Do Not...Missing: seminal | Show results with:seminal
[29]
DC-SIGN-Mediated Internalization of HIV Is Required for Trans ...
Here we show that DC-SIGN mediates rapid internalization of intact HIV into a low pH nonlysosomal compartment. Internalized virus retains competence to infect ...
[30]
Analysis of the Interaction of Ebola Virus Glycoprotein with DC-SIGN ...
Our results indicate that DC-SIGN is not an EBOV receptor but, rather, is an attachmentpromoting factor that boosts entry into B cell lines susceptible to low ...Missing: IFN suppression 2015 fullerene
[31]
The Lack of Maturation of Ebola Virus-Infected Dendritic Cells ...
Since some of these regions only weakly suppress the IFN response while strongly suppressing other components of innate immunity (38, 42, 43), we will refer to ...
[32]
DC/L-SIGN recognition of spike glycoprotein promotes SARS-CoV-2 ...
This mechanism enhances viral infection of target cells or even allow viruses to be captured by non-permissive cells for secondary presentation to permissive ...Missing: 2021-2024 | Show results with:2021-2024
[33]
CD209L/L-SIGN and CD209/DC-SIGN Act as Receptors for SARS ...
Jun 30, 2021 · We report the identification of CD209L/L-SIGN and the related protein CD209/DC-SIGN as receptors capable of mediating SARS-CoV-2 entry into human cells.
[34]
Combating DC‐SIGN‐mediated SARS‐CoV‐2 dissemination by ...
Dec 12, 2023 · An inhibition of DC-SIGN-mediated virus attachment by glycan-derived ligands has, thus, emerged as a promising strategy toward broad-spectrum antiviral ...
[35]
SARS CoV-2 spike protein variants exploit DC-SIGN/DC-SIGNR ...
May 24, 2023 · The spike Receptor Binding Domain genetic variants are thought to boost SARS CoV-2 immune evasion, resulting in its higher longevity.Missing: 2021-2024 | Show results with:2021-2024
[36]
Hepatitis C Virus Glycoproteins Interact with DC-SIGN and DC-SIGNR
HCV interactions with DC-SIGN and DC-SIGNR may contribute to the establishment or persistence of infection both by the capture and delivery of virus to the ...Missing: Dengue prM MERS-
[37]
Immature Dengue Virus Is Infectious in Human Immature Dendritic ...
The glycan moieties on prM were found to interact with DC-SIGN, thereby facilitating virus binding and cell entry. In view of the above studies we here assessed ...
[38]
The role of DC-SIGN as a trans-receptor in infection by MERS-CoV
DC-SIGN is a C-type lectin expressed in myeloid cells such as immature dendritic cells and macrophages. Through glycan recognition in viral envelope ...
[39]
https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2023.1177270/full
[40]
Mycobacteria Target DC-SIGN to Suppress Dendritic Cell Function
... IL-10 by ManLAM–DC-SIGN demonstrates that in human M. tuberculosis may target DC-SIGN to suppress cellular immune responses since both immature DCs and IL-10 ...
[41]
Article Molecular recognition of Escherichia coli R1-type core ...
Feb 16, 2024 · DC-SIGN binds to the purified deacylated R1 lipooligosaccharide mainly through the recognition of its outer core pentasaccharide, which acts as a crosslinker.
[42]
DC-SIGN Mediates the Interaction Between Neutrophils and ...
Oct 31, 2021 · Objective: We sought to investigate how PMNs and infected DCs interact in an in vitro model of Leishmania amazonensis infection. Material and ...Missing: transmigration | Show results with:transmigration
[43]
DC-SIGN mediated internalisation of glycosylated extracellular ...
Here we demonstrate that EVs released by S. mansoni schistosomula are internalised by human monocyte-derived dendritic cells (moDCs).
[44]
Dendritic Cell Interaction with Candida albicans Critically Depends ...
DC-SIGN is known to bind high mannose moieties (47). To determine the PAMP structures specifically recognized by DC-SIGN on the C. albicans cell wall, we ...
[45]
C-type Lectins - Essentials of Glycobiology - NCBI - NIH
C-type lectins in myeloid cells include in group II, DC-SIGN (in humans, but ... type lectins and may have evolved to promote interactions with MHC class I ...HISTORICAL BACKGROUND... · THE MYELOID C-TYPE... · THE SELECTINS
[46]
The C‐type lectin‐like domain superfamily - Zelensky - FEBS Press
Dec 6, 2005 · In human genome hCD23 and hDC-SIGN are closely linked. DC-SIGN is responsible for HIV particle transfer and in-trans infection of T-cells [133].
[47]
The evolutionary history of the CD209 (DC-SIGN) family in humans ...
Jun 5, 2008 · The CD209 gene family that encodes C-type lectins in primates includes CD209 (DC-SIGN), CD209L (L-SIGN) and CD209L2.
[48]
https://pmc.ncbi.nlm.nih.gov/articles/PMC2701223/
[49]
DC-SIGN activation mediates the differential effects of SAP and CRP ...
Our data suggest that SAP activates DC-SIGN to regulate the innate immune system differently from CRP, and that DC-SIGN is a target for antifibrotics.
[50]
A murine DC-SIGN homologue contributes to early host defense ...
Sep 21, 2009 · SIGNR3 binding to ManLAM and M. tuberculosis induces the secretion of IL-6 and TNF. Lung inflammatory cytokines play a crucial role in host ...
[51]
Isolation and characterization of the human DC-SIGN and DC ...
The DC-SIGN promoter is contained within nucleotides +251 to +487. AP-1, Sp1, Ets-1, and NF-κB binding sites in the DC-SIGN promoter appear to be important for ...
[52]
DC-SIGN (CD209) expression is IL-4 dependent and is ... - PubMed
These results demonstrate that DC-SIGN, considered as a MDDC differentiation marker, is a molecule specifically expressed on IL-4-treated monocytes.Missing: transcriptional promoter NF- κB Sp1
[53]
Epigenetic modulation of the immune function: A potential target for ...
This process is regulated by the acquisition of an active histone mark (H3K9Ac) in CD209 gene along with the loss of repressive marks (H3K9me3, H4K20me3) and ...
[54]
MicroRNA-155 Modulates the Pathogen Binding Ability of Dendritic ...
Here we show how miR-155 participates in the maturation of human dendritic cells (DC) and modulates pathogen binding by down-regulating DC-specific ...
[55]
Role of Long Noncoding RNAs in the Regulation of Cellular Immune ...
Nov 17, 2022 · LncRNA MALAT1 promotes the production of DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) and interleukin (IL)-10 by ...3. Role Of Lncrnas At The... · 3.1. Role Of Lncrnas In... · 4. Role Of Lncrnas In...Missing: CD209 | Show results with:CD209<|control11|><|separator|>
[56]
Promoter Variation in the DC-SIGN–Encoding Gene CD209 Is ...
Jan 3, 2006 · Variation in the gene (called CD209) that codes for DC-SIGN influences the risk of someone infected with M. tuberculosis getting sick.<|control11|><|separator|>
[57]
DC-SIGN (CD209)-mediated interactions between bacteria, lung ...
Jun 21, 2025 · DC-SIGN (CD209)-mediated interactions between bacteria, lung cancer tissues, and macrophages promote cancer metastasis.
[58]
Clinical Significance of Nodal DCsign Expression in Non-small-cell ...
Conclusion: The nodal DC morphology appears useful as a prognostic factor and may lead to a new phase of clinicopathological studies of solid cancers.Missing: NSCLC | Show results with:NSCLC
[59]
Targeting self- and foreign antigens to dendritic cells via DC-ASGPR ...
Jan 2, 2012 · In support of this, signals via DC-SIGN induce IL-10 only when DCs are activated via DC-SIGN in the presence of other Toll-like receptor– or ...
[60]
A novel CD209 polymorphism is associated with rheumatoid arthritis ...
Apr 1, 2021 · The higher expression of CD209 on immune cells correlates with the severity of cartilage destruction in patients with rheumatoid arthritis (RA).
[61]
Identification of CD209 as an Intervention Target for Type 2 Diabetes ...
Protein CD209 and central obesity potentially play a crucial role between COVID-19 susceptibility and T2D. Our results highlight CD209 as a potential ...Missing: persistent inflammation
[62]
Liver Sinusoidal Endothelial Cells in Hepatic Fibrosis - PMC
Restoration of LSEC differentiation in vivo promotes HSC quiescence, enhances regression of fibrosis, and prevents progression of cirrhosis.
[63]
DC-SIGN promotes allergen uptake and activation of dendritic cells ...
The aim of this study is to explore the role of DC-SIGN in capturing and processing glycan-containing allergens and in the subsequent DC activation and T helper ...Missing: function | Show results with:function