title: Alpha 4 integrin signaling activates phosphatidylinositol 3-kinase and stimulates T cell adhesion to intercellular adhesion molecule-1 to a similar extent as CD3, but induces a distinct rearrangement of the actin cytoskeleton.
abstract: Dynamic regulation of beta(2) integrin-dependent adhesion is critical for a wide array of T cell functions. We previously showed that binding of high-affinity alpha(4)beta(1) integrins to VCAM-1 strengthens alpha(L)beta(2) integrin-mediated adhesion to ICAM-1. In this study, we compared beta(2) integrin-mediated adhesion of T cells to ICAM-1 under two different functional contexts: alpha(4) integrin signaling during emigration from blood into tissues and CD3 signaling during adhesion to APCs and target cells. Cross-linking either alpha(4) integrin or CD3 on Jurkat T cells induced adhesion to ICAM-1 of comparable strength. Adhesion was dependent on phosphatidylinositol (PI) 3-kinase but not p44/42 mitogen-activated protein kinase (extracellular regulated kinase 1/2), because it was inhibited by wortmannin and LY294002 but not U0126. These data suggest that PI 3-kinase is a ubiquitous regulator of beta(2) integrin-mediated adhesion. A distinct morphological change consisting of Jurkat cell spreading and extension of filopodia was induced by alpha(4) integrin signaling. In contrast, CD3 induced radial rings of cortical actin polymerization. Inhibitors of PI 3-kinase and extracellular regulated kinase 1/2 did not affect alpha(4) integrin-induced rearrangement of the actin cytoskeleton, but treatment with ionomycin, a Ca(2+) ionophore, modulated cell morphology by reducing filopodia and promoting lamellipodia formation. Qualitatively similar morphological and adhesive changes to those observed with Jurkat cells were observed following alpha(4) integrin or CD3 stimulation of human peripheral blood T cells.
authors.affiliation: Toronto General Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. sharon.hyduk@utoronto.ca
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Hyduk
authors.forename: Myron I
authors.initials: MI
authors.lastname: Cybulsky
mesh_terms: D000199:Actins / Q000378:metabolism*; D015703:Antigens, CD / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000276:immunology; D002469:Cell Separation; D003599:Cytoskeleton / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D039441:Integrin alpha4; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D019169:Jurkat Cells; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*
chemical_list: D000199:Actins; D015703:Antigens, CD; D018821:CD18 Antigens; D017252:CD3 Complex; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases