An atlas of human siglecs integrates expression, affinity, and cis/trans sialoglycan recognition profiles.

All living cells have a sugar-coat that facilitates communication. Sialic acids cap mammalian glycans and are recognized by immune cells through sialic acid-binding immunoglobulin-like lectins (Siglecs) that regulate signaling by their cytoplasmic motifs. Inconsistent reports of Siglecs expression and sialoglycan recognition limit their therapeutic potential. Here we investigate 14 functional human Siglecs for their expression, glycan interactions and affinities. SIGLEC mRNA is broad in blood-derived monocytes and dendritic cells, restricted in natural-killer/B cells and absent in T cells, with similar Siglec-proteins expression in splenocytes. Binding to 114 glycans across 274 glycan microarrays, 220 splenocytes-assays and 132 cell-based arrays, reveal Siglecs functional relationships. Siglec-sialoglycan interactions are affected by sialic acid type (N-acetylneuraminic acid and N-glycolylneuraminic acid), 9-O-acetylation, linkage, sulfation, and carrier, are of varying affinities ( ~ 10 nM to µM/mM), and cis interactions are key regulatory features. This functional atlas enhances Siglecs potential as biomarkers and immunotherapy targets, switches or immune checkpoints for cancer and other diseases.