REGULATION OF L-SELECTIN-MEDIATED ROLLING THROUGH RECEPTOR DIMERIZATION

L-selectin binding activity for its ligand expressed by vascular endot helium is rapidly and transiently increased after leukocyte activation . To identify mechanisms for upregulation and assess how this influenc es leukocyte/endothelial cell interactions, cell-surface dimers of L-s electin were induced using the coumermycin-GyrB dimerization strategy for cross-linking L-selectin cytoplasmic domains in L-selectin cDNA-tr ansfected lymphoblastoid cells. Coumermycin-induced L-selectin dimeriz ation resulted in an approximately fourfold increase in binding of pho sphomanan monoester core complex (PPME), a natural mimic of an L-selec tin ligand, comparable to that observed after leukocyte activation. Mo reover, L-selectin dimerization significantly increased (by similar to 700%) the number of lymphocytes rolling an vascular endothelium under a broad range of physiological sheer stresses, and significantly slow ed their rolling velocities. Therefore, L-selectin dimerization may ex plain the rapid increase in ligand binding activity that occurs after leukocyte activation and may directly influence leukocyte migration to peripheral lymphoid tissues or to sites of inflammation. Inducible ol igomerization may also be a common mechanism for rapidly upregulating the adhesive or ligand-binding function of other cell-surface receptor s.