Roles of sulfated glycans in lymphocyte homing

Lymphocyte homing is mediated by a specific interaction between the lymphocyte homing receptor L-selectin and its sulfated glycoprotein ligands, which are expressed on high endothelial venules (HEV) in the lymph nodes. To examine the significance of the sulfation of L-selectin ligands, our group has generated gene-targeted mice deficient in both N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST)-1 and GlcNAc6ST-2. The mutant mice show approximately 75% less lymphocyte homing to the peripheral lymph nodes than normal, indicating that GlcNAc6ST-1 and GlcNAc6ST-2 play a major role in the biosynthesis of L-selectin ligand in HEV. In agreement with this interpretation, an oligosaccharide analysis indicated that 6-sulfo sialyl Lewis X, a major L-selectin ligand sulfated glycan, is almost completely abrogated in the double-deficient mice. Lymphocyte homing into the parenchyma of lymph nodes is mediated by a series of interactions: rolling, activation by chemokines, integrin-mediated adhesion, and transmigration. During the rolling interaction, which is mediated by L-selectin and sulfated glycans, lymphocytes receive activation signals from chemokines presented on the surface of HEV by heparan sulfate, a sulfated glycosaminoglycan, which leads to the activation of lymphocyte beta2 integrin. Sulfated glycans are thus involved in both the rolling and the chemokine-induced activation steps between lymphocytes and HEV. In this article, recent findings on the roles of sulfated glycans in both of these lymphocyte-homing steps will be reviewed. The possible application of sulfated glycans for the prevention of inflammatory disorders will also be discussed.