Mechanisms regulating leukocyte rolling mediated by selectin ligand PSGL-1

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Leukocytes migrate from the blood into non-lymphoid tissues through a multi-step process that involves cell rolling, arrest, and transmigration. Although the role of P-selectin glycoprotein ligand-1 (PSGL-1), a major ligand for P-selectin expressed on leukocytes, as a rolling receptor has been clarified, the mechanisms regulating the PSGL-1-mediated rolling and the transition from rolling to arrest are not well understood. In this research project, we clarified two PSGL-1-mediated mechanisms that can regulate the transition form rolling to arrest. The first mechanism is the PSGL-1-mediated stimulation of LFA-1-dependent cell adhesion. We showed that antibody-mediated cross-linking of the PSGL-1 on Th1 cells enhances LFA-1-dependent cell binding to ICAM-1. Combined stimulation by PSGL-1 cross-linking and the Th1-stimulating chemokine CXCL10 (IP-10) or CCLS (RANTES) showed a more-than additive effect on LFA-1-mediated Th1 cell adhesion as well as on LFA-1 redistribution on the cell surface. Moreover, PSGL-1-mediated rolling on P-selectin enhanced the Th1 cell accumulation on ICAM-1 under flow conditions. These results support the idea that PSGL-1-mediated rolling interactions induce intracellular signals leading to integrin activation, facilitating Th1-cell arrest and subsequent migration into target tissues. The second mechanism is the interaction of PSGL-1 with chemokines. We showed that human PSGL-1 interacts with CCL27 (CTACK), and that sulfated tyrosines play a critical role in the CCL27-PSGL-1 interaction. Functionally, PSGL-1 reduced the chemotaxis of L1.2 cells expressing CCR10, the receptor for CCL27. Regulation of chemokine-mediated responses by PSGL-1 may affect the transition from rolling to chemokine-mediated arrest during leukocyte migration.