Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity [mouse]. Mus musculus

C-type lectin receptors (CLRs) are a large family of immunoreceptors that recognizes polysaccharides exposed on pathogens and triggers innate immune responses. However, the ligand spectrums of the whole members have not been fully understood. In this study, we found that seaweed-derived fucan activates cells expressing human Dectin-1 but not mouse Dectin-1. In fucan, low-valency β-glucan appeared to represent this activity, as the ligand activity was eliminated by the treatment of westase, a β-glucanase. Another low-valency β-glucan, laminarin, also acts as an agonist on human Dectin-1 but not for mouse Dectin-1, whereas high-valency β-glucan curdlan activated both human and mouse Dectin-1. Reciprocal mutagenesis analysis revealed that the ligand-binding domain of human Dectin-1 did not determine its unique sensitivity to low-valency β-glucan. Rather, its intracellular domain contributes to render human Dectin-1 reactive to low-valency β-glucan. Within the hDectin-1 intracellular domain, only two amino acids, Glu2 and Pro5, were sufficient to confer sensitivity on mouse Dectin-1. Conversely, the introduction of mouse-type amino acids, Lys2 and Ser5, to human Dectin-1 reduced the reactivity. These results suggest that the intracellular domain, but not the ligand binding domain, of Dectin-1 modulate their functions which determine the ligand spectrum. Overall design: To confirm the hDectin-1 specific phenomenon using primary cells, we stimulated human monocyte-derived dendritic cells (hMoDCs) and mouse bone marrow-derived dendritic cells (mBMDCs) with laminarin, and compare the gene expression.