The Dendritic Cell-Specific Adhesion Receptor DC-SIGN Internalizes Antigen for Presentation to T Cells

Abstract

Dendritic cells (DCs) capture Ags or viruses in peripheral tissue to transport them to lymphoid organs to induce cellular T cell responses. Recently, a DC-specific C-type lectin was identified, DC-specific ICAM-grabbing non-integrin (DC-SIGN), that functions as cell adhesion receptor mediating both DC migration and T cell activation. DC-SIGN also functions as an HIV-1R that captures HIVgp120 and facilitates DC-induced HIV transmission of T cells. Internalization motifs in the cytoplasmic tail of DC-SIGN hint to a function of DC-SIGN as endocytic receptor. In this study we demonstrate that on DCs DC-SIGN is rapidly internalized upon binding of soluble ligand. Mutating a putative internalization motif in the cytoplasmic tail reduces ligand-induced internalization. Detailed analysis using ratio fluorescence imaging and electron microscopy showed that DC-SIGN-ligand complexes are targeted to late endosomes/lysosomes. Moreover, ligands internalized by DC-SIGN are efficiently processed and presented to CD4+ T cells. The distinct pattern of expression of C-type lectins on DCs in situ and their nonoverlapping Ag recognition profile hint to selective functions of these receptors to allow a DC to recognize a wide variety of Ags and to process these to induce T cell activation. These data point to a novel function of the adhesion receptor DC-SIGN as an efficient DC-specific Ag receptor that can be used as a target to induce viral and antitumor immunity.

Delivery of antigen using a novel mannosylated dendrimer potentiates immunogenicity in vitro and in vivo

“…Nevertheless, the affinity of MD to the C-type lectin DC-SIGN has been previously demonstrated [27]. DC-SIGN abundantly expressed in both human and mouse DC recognizes complex mannose residues and targets the late endolysosome [28][29][30].…”

Antibody‐mediated delivery of antigen to chemokine receptors on antigen‐presenting cells results in enhanced CD4+ T cell responses

“…We and others have previously studied the potency of various targets on APC for Ab-mediated delivery of Ag for MHC class II presentation. Compared with other endocytic receptors, such as DEC-205 [7], DC-SIGN [8,15], and BDCA-2 [16], which were 100-1,000-fold more potent than control mAb, certain chemokine receptors (CCR1 and CXCR4) were even more efficient (10,000-fold) at inducing T cell activation. This conclusion is supported by independent experiments in which an antagonistic chemokine (Molluscum contagiosum viral chemokine MC148) was conjugated to non-immunogenic tumor Ag.…”

Spontaneous transgenesis of human B lymphocytes

“…Examples of this type are DEC-205, 52 an endocytic receptor expressed on murine dendritic cells and B lymphocytes, 53 and DC-SIGN, a C-type lectin receptor present only on dendritic cells. 54 Interestingly, human B lymphocytes express a DEC-205 homologue (the gp200-MR6 molecule), 55 which possesses the same GFSSVRY sorting sequence as DEC-205. 52 Which of these eventualities applies to our model remains unknown and deserves future study.…”