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Chapter 5 The simultaneous triggering of DCIR and DC-SIGN hampers DC-SIGN-mediated endo-lysosomal routing

Several C-type lectins (CLRs) are expressed on dendritic cells (DCs). CLRs are carbohydrate-specific receptors involved in the recognition of glycosylated antigens. The interaction of CLRs with their ligands facilitates antigen internalization and can induce signaling or modulate TLR-induced signaling responses. Here, we investigated the internalization characteristics of four different CLRs: MR, DC-SIGN, MGL and DCIR, in order to obtain more insight in the biology of CLRs on DCs. CLR internalization and intracellular routing was measured using imaging flow cytometry. The internalization score, a measure of the internalization capacity of each CLR, was decreased for DCIR as compared to the other CLRs. In addition, DCIR-mediated antigen routing was clearly different to the intracellular compartments targeted by the other CLRs, and DCIR targeting resulted in poor CD4 + T cell stimulation. Moreover, we show that most CLRs, with the exception of DC-SIGN, are able to recycle to the cell membrane, thereby enhancing antigen uptake. Interestingly, maturation did not affect the ability of any of the CLRs to internalize; however, the recycling capacity of MGL and the expression levels of all CLRs were decreased by LPS-induced maturation. Since pathogens are covered with multiple glycan structures that could target several CLRs simultaneously, we evaluated the effect of simultaneous triggering of multiple CLRs on their internalization and routing. Although CLR internalization appeared to be independently regulated, DC-SIGN routing was affected by simultaneous DCIR triggering. In conclusion, our results provide new insights in the cell biology of CLRs and identify DCIR as a poor antigen uptake receptor.