DCIR interacts with ligands from both endogenous and pathogenic origin

• We compared the glycan specificity of the DC-expressed CLRs: DCIR and DC-SIGN.
• DCIR and DC-SIGN have overlapping glycan specificities.
• Novel DCIR ligands of endogenous and pathogen-related origin were discovered.
• Unique DCIR and DC-SIGN ligands are defined.
• The interaction of DCIR with its ligands is influenced by the glycosylation of DCIR.

C-type lectins on dendritic cells function as antigen uptake and signaling receptors, thereby influencing cellular immune responses. Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) is one of the best-studied C-type lectin receptors expressed on DCs and its glycan specificity and functional requirements for ligand binding have been intensively investigated. The carbohydrate specificity of dendritic cell immunoreceptor (DCIR), another DC-expressed lectin, was still debated, but we have recently confirmed DCIR as mannose/fucose-binding lectin. Since DC-SIGN and DCIR may potentially share ligands, we set out to elucidate the interaction of DCIR with established DC-SIGN-binding ligands, by comparing the carbohydrate specificity of DCIR and DC-SIGN in more detail. Our results clearly demonstrate that DC-SIGN has a broader glycan specificity compared to DCIR, which interacts only with mannotriose, sulfo-Lewisa, Lewisb and Lewisa. While most of the tested DC-SIGN ligands bound DCIR as well, Candida albicans and some glycoproteins on some cancer cell lines were identified as DC-SIGN-specific ligands. Interestingly, DCIR strongly bound human immunodeficiency virus type 1 (HIV-1) gp140 glycoproteins, while its interaction with the well-studied DC-SIGN-binding HIV-1 ligand gp120 was much weaker. Furthermore, DCIR-specific ligands were detected on keratinocytes. Furthermore, the interaction of DCIR with its ligands was strongly influenced by the glycosylation of DCIR. In conclusion, we show that sulfo-Lewisa is a high affinity ligand for DCIR and that DCIR interacts with ligands from both pathogenic and endogenous origin of which most are shared by DC-SIGN.