Glycan-based DC-SIGN targeting vaccines to enhance antigen cross-presentation

► Leb and LeX glycans achieve an efficient antigen-targeting to DCs through DC-SIGN. ► Glycan multivalency is a necessary condition for efficient targeting. ► DC-SIGN targeting results in robust CD4+ and CD8+ T cell responses. Dendritic cells are the most efficient professional antigen-presenting cells in pathogen recognition and play a pivotal role in the control of the immune response. Pathogen recognition is ensured by the expression of a vast variety of pattern-recognition receptors. Amongst them are C-type lectins, a large family of receptors characterized by a domain that – in many cases – mediates calcium-dependent glycan binding. C-type lectins facilitate antigen uptake for efficient processing and presentation and, in some cases, also trigger signaling to modulate T cell responses. These properties make C-type lectin receptors ideal candidates for the targeting of antigens to dendritic cells for vaccination. DC-SIGN is a paradigmatic example of C-type lectin receptors on dendritic cells that facilitate vaccination strategies. DC-SIGN is highly expressed on immature conventional dendritic cells, particularly at the mucosa and the dermis, where DCs first encounter pathogens, but also can easily be accessed for vaccination. Upon ligand binding, DC-SIGN rapidly internalizes and directs its cargo into the endo-lysosomal pathway, which results in MHC-II presentation. But antigens targeted to DC-SIGN are also presented efficiently to CD8+ T cells, suggesting there is an additional endocytic route that leads to cross-presentation. Simultaneous triggering of DC-SIGN and TLRs results in the modulation of cytokine responses and facilitates cross-presentation to enhance CD4+ and CD8+ T cell responses. Because the glycan specificity of DC-SIGN has been characterized in detail, glycans can be used for the targeting of antigens to DCs in a DC-SIGN-dependent manner. Glycans represent a great advantage over monoclonal antibodies, they diminish the risk of side effects, are very small, and their production can rely entirely in organic chemistry approaches. Here, we discuss the capacity of glycan-based vaccines to enhance antigen-specific CD4+ and CD8+ T cell responses in human skin and mouse model systems.