Molecular mechanisms of adhesive interactions between HEV and lymphocytes that regulate homeostatic lymphocyte homing.

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Lymphocyte homing to lymph nodes and Peyer's patches is mediated by cascade adhesive interactions between circulating lymphocytes and high endothelial venules (HEVs). The initial phase of the HEV-lymphocyte interaction is mainly governed by the lymphocyte adhesion molecule L-selectin, which recognizes sulfated and sialylated O-linked oligosaccharide displayed by sialomucin core proteins expressed by HEVs. Here we investigated HEV specific cell adhesion mechanisms that regulate homeostatic lymphocyte homing to lymph nodes and Peyer's patches. By gene expression profiling of mouse HEVs, we identified two novel HEV associated sialomucins, endomucin and nepmucin. Molecular cloning and nucleotide sequencing revealed that endomucin contains a mucin-like domain in its extracellular region, whereas nepmucin contains a mucin-like domain and an Ig domain. Interestingly, while endomucin is expressed in vascular endothelial cells in a variety of tissues, nepmucin is expressed in those in peripheral lymph nodes but not in Peyer's patches. In lymph node HEVs, both endomucin and nepmucin are decorated with L-selectin-reactive sugar chains and can bind soluble L-selectin. Furthermore, upon appropriate glycosylation by a specific combination of sugar-modification enzymes, including C2GnT, FucTVII, and LSST, endomucin and nepmucin can display L-selectin-reactive oligosaccharides in their mucin-domain and support lymphocyte rolling under physiological flow conditions in vitro. In addirion, the Ig-domain of nepmucin appears directly support lymphocyte binding. These observations collectively suggest that endomucin and nepmucin represent novel mucin-type ligands for L-selectin in HEVs and that they play important role in lymphocyte tracking via HEVs.