LIGATION OF L-SELECTIN THROUGH CONSERVED REGIONS WITHIN THE LECTIN DOMAIN ACTIVATES SIGNAL-TRANSDUCTION PATHWAYS AND INTEGRIN FUNCTION IN HUMAN, MOUSE, AND RAT LEUKOCYTES

L-selectin is a cell surface adhesion receptor that mediates leukocyte rolling along vascular endothelium at sites of inflammation and lymph ocyte attachment to endothelial cells within peripheral lymphoid tissu es, Since ligation of L-selectin through its ligand recognition region may mimic physiologic ligand binding, a new panel of mAbs that engage d a conserved ligand-binding region within the lectin domains of human , mouse, and rat L-selectin were generated using L-selectin-deficient mice. Indeed, appropriate ligation of L-selectin generated transmembra ne signals that resulted in immediate intercellular adhesion following cell-cell contact of lymphocytes, neutrophils, and L-selectin cDNA-tr ansfected cells, Ab binding to only some epitopes within the lectin do main of L-selectin induced adhesion, while mAb binding to numerous oth er epitopes or other domains of L-selectin had no effect, PPME (yeast polyphosphomonoester core polysaccharide), a complex carbohydrate that mimics the natural L-selectin ligand, also induced potent intercellul ar adhesion, The induction of intercellular adhesion required cellular energy, an intact cytoskeleton, and cytoplasmic kinase activity as we ll as the membrane proximal and cytoplasmic domains of L-selectin, The refore, ligation of L-selectin through specific ligand-binding epitope s identified by the mAbs generated in this study can generate transmem brane signals, Signaling through L-selectin may enhance leukocyte-endo thelial cell interactions by serving as an activation/priming step dur ing rolling, thereby promoting subsequent firm cell-cell adhesion in t he presence of inflammatory mediators.