Targeting Antigens to Dendritic Cell Receptors for Vaccine Development

Table 1

Summary of dendritic cell receptors targeted for vaccine development: C-type lectin receptors.

Receptor	Designation	Function
1. Group 1 C-type lectin receptors
1.1. Mannose receptor	CD206	Expressed on macrophages and DCs. Binds to mannan, mannose, fucose, glucose, maltose, GlcNAc, lipoarabinomannan, cell wall of yeast, viruses, and bacteria leading to phagocytosis/endocytosis. Used to target protein, peptides, DNA, dendrimers, liposomes, and anti-MR antibodies for vaccine development with Th1, Th2, CTL, and Ab responses induced. Targeting antigens to MR using mannan has been used in human clinical trials.
2. Group 2 C-type lectin receptors
2.1.  Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)	CD209; Clec4L	Expressed on immature DCs, macrophages endothelial vascular cells, atherosclerotic plaques, and lymphatic vessels, not on placmacytoid DCs. Binds to mannan, mannose, fucose, GlcNAc, GalNAc, yeast, lewis blood group antigens Le^x, HIV-1 gp120, ebola virus, hepatitis C virus, dengue virus, respiratory syncytial virus, measles virus, Mycobacterium tuberculosis, Leishmania amastigote, Helicobacter pylori, Leishmania mexicana, Schistosoma mansoni, Porphyromonas gingivalis, Neisseria gonorrhoeae, Candida albicans, house dust mite (Der p1), and dog allergens (Can f1). Interacts with ICAM-3 and ICAM-2. Targeting DC-SIGN using antigen linked to anti-DC-SIGN antibodies, Manalpha-6 Man, lactoside, and Lewis oligosaccharide, stimulates T-cell and/or antibody responses, and has been studied as a potential receptor for vaccine targeting. Eight murine homologues identified, SIGN-R1 (CD209b) to SIGN-R8.
2.1.1. L-SIGN or DC-SIGNR	CD299; CD209L; Clec4M	Expressed on liver sinusoidal cells, lymph nodes, and endothelial vascular cells, but not on DCs. Binds to HIV gp120, Man9GlcNAc2, HIV, simian immunodeficiency virus, ebola virus, hepatitis C virus, and respiratory syncytial virus. Targeting L-SIGN with anti-L-SIGN antibodies induces T-cell responses. Targeting L-SIGN shows promise for the development of targeted vaccines.
2.1.2.  Liver and lymph node sinusoidal cell type lectin (LSECtin)	Clec4G	Expressed in liver, lymph nodes, sinusoidal endothelial cells, DCs, and Kupffer cells. Binds to N-acetyl-glucosamine, fucose, ebola virus, filovirus glycoproteins, lymphocytic choriomeningitis virus, S-protein of SARS coronavirus, and to CD44, but not to mannose, HIV, and hepatitis C. Coexpressed with DC-SIGNR and CD23. Antibody or ligand-mediated engagement of LSECtin activates rapid internalization, indicating that LSECtin may be a suitable receptor for targeting antiges in the development of vaccination regimes.
2.1.3. C-type lectin immune receptor (CIRE); (murine homologue of DC-SIGN)	CD209	Expressed by immature CD8− splenic DCs (CD8−CD4+ and CD8−CD4−), on some CD4+ DCs, plasmacytoid pre-DCs, and not by, CD8+ DCs, macrophages, or monocytes. It is a ligand for ICAM-3 and binds to HIV. Polyanhydride nanoparticles covalently linked to dimannose and lactose matures DCs and are internalized by DCs. CIRE shows promise as an appropriate target for antigen delivery for improved vaccine development.
2.2. Langerin	CD207; Clec4K	Expressed on Langerhans cells, CD103+ DCs, and splenic CD8+ DCs. Binds to mannose and internalizes mannose residues into Birbeck granules, where Langerin is expressed. Anti-Langerin antibody targeting antigens to Langerin is endocytozed in vitro and in vivo and induces Th1 and antibody responses.
2.3. MGL; (human macrophage galactose- and N-acetylgalactosamine-specific C-type lectin)		Expressed on macrophages, immature DCs galactose, GalNAc, Tn antigen, filoviruses, and gonorrhea. GalNAc modified peptides to target MGL receptor expressed on murine and human DCs, which stimulates T-cell and antibody responses, and this approach could be used to design novel anticancer vaccines.
2.4. Dectin-1 or beta-glucan receptor; (DC-associated C-type lectin-1)	DCAL-1; Clec7A	Expressed on myeloid DCs, CD8−CD8− DCs, dermal DCs, monocytes, macrophages, neutrophils, T cells, B cells, mast cells, eosinophils, and monocytes. Binds to beta-glucan on yeast, mycobacteria, plant cell walls, Saccharomyces, Candida, Pneumocystis, Coccidioides, Penicillium, and Aspergillus, but not Cryptococcus fungal species, and interacts with CD37. Anti-Dectin-1 and anti-Dectin-2 antibodies linked to proteins stimulate CD8+ and CD4+ T cells, and immunization with beta-glycan modified proteins induces CD4+ and Th17 bias responses.
2.4.1. DNGR-1; (NK lectin group receptor-1)	Clec9A	Expressed on murine CD8+ DCs not on CD4+ DCs, on CD11c+ DCs but not by CD11c− cells (B cells, T cells, NK cells, NKT cells, macrophages, and granulocytes), on plasmacytoid DCs, and on human blood DCsBDCA-3+ DCs) and monocytes (CD14+CD16−). Highly expressed on Flt3 ligand bone marrow derived CD8+ DCs. Target for immune response induction.
2.4.2. Myeloid inhibitory C-type lectin receptor (MICL)	Clec12A	Homologous to Dectin-1 and part of Dectin-1 cluster. Also termed as CLL-1, DCAL-2, and KLRL1. Expressed on granulocytes, monocytes, macrophages, B cells, CD8+ T cells in peripheral blood, and DCs.
2.4.3.  C-type lectin-like receptor 2 (CLEC2)	Clec1B	Expressed on NK cells, monocytes, granulocytes, platelets, megakaryocytes, and liver sinusoidal epithelial cells. Binds to HIV-1 and facilitates HIV-1 spread to other cells and binds to snake venom rhodocytin. Not much is known regarding stimulating immune responses; however, colocalization with DC-SIGN suggests that it may have an immune stimulatory effect.
2.4.4. CLEC12B; (macrophage antigen H)	Clec21B	Part of the NK gene complex/dectin-1 cluster of C-type lectin receptors. Expressed on macrophages, monocytes, and DCs. Not much is known regarding its function.
2.4.5. LOX-1; (Lectin-like receptor for oxidized density lipoprotein-1)	Clec8A	Part of the dectin-1 cluster of C-type lectin receptors and scavenger receptor family. Expressed on endothelial cells, smooth muscle cells, platelets, fibroblasts, and macrophages. Binds to Gram-positive and Gram-negative bacteria, oxidized LDL modified lipoproteins, phospholipids, apoptotic cells, C-reactive protein, and heat shock protein (HSP)-70. Targeting LOX-1 induces immune responses and is a promising target for cancer immunotherapy.
2.5. DC immunoreceptor subfamily
2.5.1. DC immunoreceptor (DCIR)	Clec4A	Expressed on plasmacytoid DCs, immature and mature monocyte-derived DCs monocytes, macrophages, and B cells. Binds to TLR9. Targeting DCIR stimulates immune responses especially CD8+ T cells.
2.5.2. Dectin-2; (or beta-glucan receptor)	DCAL-2; Clec6A	Expressed on DCs, macrophages neutrophils, and monocytes. Binds to beta1,3 and beta1,6-linked glucans on yeast, mycobacteria, and plant cell walls. Targeting dectin-2 stimulates immune responses in mice.
2.5.3. Blood DC antigen (BDCA-2)	Clec4C	Expressed on human blood DCs. Targeting BDCA-2 suppresses IFN-alpha/beta cytokine secretion.