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 (Gal1-4GlcNAc-R), are abundant on PMNs, the presence of type 1 Gal1-3GlcNAc-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 1-3 galactosyltransferase and 1-4 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 1-4 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.