The physiological role of DC-SIGN: A tale of mice and men

• DC-SIGN is a multifunctional C-type lectin receptor on antigen-presenting cells.
• Its functions include adhesion, migration, signaling, and antigen uptake/presentation.
• All evidence supporting DC-SIGN functions is based on in vitro assays.
• The absence of a functional DC-SIGN ortholog hampers the study of its physiological role.

The innate immune receptor DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin) was discovered over a decade ago and was initially identified as a pattern recognition receptor. In addition to its ability to recognize a broad range of pathogen-derived ligands and self-glycoproteins, DC-SIGN also mediates intercellular adhesion, as well as antigen uptake and signaling, which is a functional hallmark of dendritic cells (DCs). Most research on DC-SIGN has relied on in vitro studies. The in vivo function of DC-SIGN is difficult to address, in part because there are eight genetic homologs in mice with no clear DC-SIGN ortholog. Here, we summarize the functions attributed to DC-SIGN based on in vitro data and discuss the limitations of available mouse models to uncover the physiological role of this receptor in vivo.