title: Rolling of Th1 cells via P-selectin glycoprotein ligand-1 stimulates LFA-1-mediated cell binding to ICAM-1.
abstract: Activated T cells migrate from the blood into nonlymphoid tissues through a multistep process that involves cell rolling, arrest, and transmigration. P-Selectin glycoprotein ligand-1 (PSGL-1) is a major ligand for P-selectin expressed on subsets of activated T cells such as Th1 cells and mediates cell rolling on vascular endothelium. Rolling cells are arrested through a firm adhesion step mediated by integrins. Although chemokines presented on the endothelium trigger integrin activation, a second mechanism has been proposed where signaling via rolling receptors directly activates integrins. In this study, we show that Ab-mediated cross-linking of the PSGL-1 on Th1 cells enhances LFA-1-dependent cell binding to ICAM-1. PSGL-1 cross-linking did not enhance soluble ICAM-1 binding but induced clustering of LFA-1 on the cell surface, suggesting that an increase in LFA-1 avidity may account for the enhanced binding to ICAM-1. Combined stimulation by PSGL-1 cross-linking and the Th1-stimulating chemokine CXCL10 or CCL5 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. PSGL-1 cross-linking induced activation of protein kinase C isoforms, and the increased Th1 cell adhesion observed under flow and also static conditions was strongly inhibited by calphostin C, implicating protein kinase C in the intracellular signaling in PSGL-1-mediated LFA-1 activation. 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.
authors.affiliation: Laboratory of Molecular and Cellular Recognition, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Atarashi
authors.forename: Takako
authors.initials: T
authors.lastname: Hirata
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Kanemitsu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyasaka
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001666:Binding Sites, Antibody; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019742:Chemokines, CC / Q000494:pharmacology; D019743:Chemokines, CXC / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012212:Rheology / Q000379:methods; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D018417:Th1 Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C483024:CCL5 protein, human; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019742:Chemokines, CC; D019743:Chemokines, CXC; D003432:Cross-Linking Reagents; D007074:Immunoglobulin G; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1; D011493:Protein Kinase C