Sulfated Sugars for Rolling Lymphocytes

The recirculation of naive lymphocytes from the blood to LNs then back to the blood through the efferent lym-phatics increases the likelihood that rare antigen-specific cells will encounter their specific antigen. Circulating lym-phocytes enter the LNs at specialized postcapillary venules known as high endothelial venules (HEVs). Homing to HEVs is thought to occur in three steps. First, lymphocytes adhere loosely and roll along the endothelium. Next, they are activated by chemokines presented on endothelial pro-teoglycans. Finally, increased integrin affinity and avidity, triggered by chemokine signaling, leads to firm adhesion and arrest of the activated cells. The C-type lectin L-selectin is required for naive lymphocyte homing to peripheral LNs (1), and LNs are small and hypocellular in mice lacking this adhesion molecule (2). More specifically, L-selectin is the main receptor responsible for the rolling of these cells in HEVs. The rapid and reversible binding of L-selectin to carbohydrate-containing ligands expressed on the luminal surface of high endothelial venules results in the rolling of lymphocytes in the direction of blood flow. Several glycoproteins that may serve as L-selectin ligands have been identified, including CD34, sgp200, endomucin, and possibly GlyCAM-1 (3). The absence of an overt defect in lymphocyte homing to peripheral nodes in CD34 knockout mice (4) indicates that there might be a high level of redundancy in the system. MECA-79 is a mAb that reacts with L-selectin ligands, stains high endothelial venules, and blocks L-selectin–dependent lymphocyte homing (5). Since blocking with MECA-79 and L-selectin– specific antibodies does not appear to have additive effects on lymphocyte homing, glycoproteins that carry the MECA-79 antigen, which is known as peripheral node addressin, have been considered to be the relevant L-selectin ligands. However, the papers by van Zante et al. (6) and M'Rini et al. (7) in this issue challenge this view. A New Class of L-selectin Ligand. Similar to other selectin ligands, the function of L-selectin ligands depends on post-translational modifications. Two fucosyl transferases, FucT-IV and FucT-VII, and at least one sulfotransferase, GlcNAc-6-O-sulfotransferase (HEC-GlcNAc6ST), contribute to the biosynthesis of the active carbohydrate chains that are recognized by L-selectin. In reconstitution experiments in flow chambers, CD34–IgG fusion protein harvested from cells cotransfected with FucT-VII and HEC-GlcNAc6ST supported L-selectin–dependent rolling (8), but it is not known whether the modifications generated by these enzymes account for all L-selectin–dependent rolling activity in vivo. L-selectin also binds to P-selectin glycoprotein ligand-1 (PSGL-1) that is sulfated on tyrosine residues (9, …