Expression of lewis-a glycans on polymorphonuclear leukocytes augments function by increasing transmigration

PMN-expressed fucosylated glycans from the Lewis glycan family, including Lewis-x (Le^x) and sialyl Lewis-x (sLe^x), have previously been implicated in the regulation of important PMN functions, including selectin-mediated trafficking across vascular endothelium. Although glycans, such as Le^x and sLe^x, which are based on the type 2 sequence (Galβ1-4GlcNAc-R), are abundant on PMNs, the presence of type 1 Galβ1-3GlcNAc-R glycans required for PMN expression of the closely related stereoisomer of Le^x, termed Lewis-A (Le^a), has not, to our knowledge, been reported. Here, we show that Le^a is abundantly expressed by human PMNs and functionally regulates PMN migration. Using mAbs whose precise epitopes were determined using glycan array technology, Le^a function was probed using Le^a-selective mAbs and lectins, revealing increased PMN transmigration across model intestinal epithelia, which was independent of epithelial-expressed Le^a. Analyses of glycan synthetic machinery in PMNs revealed expression of β1-3 galactosyltransferase and α1–4 fucosyltransferase, which are required for Le^a synthesis. Specificity of functional effects observed after ligation of Le^a was confirmed by failure of anti-Le^a mAbs to enhance migration using PMNs from individuals deficient in α1–4 fucosylation. These results demonstrate that Le^a is expressed on human PMNs, and its specific engagement enhances PMN migration responses. We propose that PMN Le^a represents a new target for modulating inflammation and regulating intestinal, innate immunity.