Feedback modulation of ligand-engaged alpha L/beta 2 leukocyte integrin (LFA-1) by cyclic AMP-dependent protein kinase.
Rapid interconversion between a firmly adherent and a nonadherent, circulating phenotype is a distinctive feature of mature leukocytes and is thought to be essential for efficient immune surveillance. Leukocyte adhesion is a finely regulated process controlled in part by reversible, activation-dependent up-regulation of beta 1- and beta 2- integrin function. To investigate the molecular basis of such reversibility in human T lymphocytes, we developed a model of alpha L/beta 2 (LFA-1)-dependent adhesion that uses a heterologous cell line expressing human intercellular adhesion molecule-1 as a selected ligand. We show here that intracellular cAMP elevation, followed by cAMP-dependent kinase activation, promotes T cell deadhesion by disassembling the actin-based cytoskeleton, thus dissociating LFA-1 from cytoskeletal anchoring proteins that normally connect the adhesion receptor to F-actin in lymphocytes engaged in intercellular adhesion. Cells costimulated via the CD3 and LFA-1 receptors by specific Abs or by binding to intercellular adhesion molecule-1 display gradual and persistent intracellular cAMP elevations due to the synergistic induction of a protein kinase C-dependent adenylyl cyclase isoform. On the basis of these findings, we propose a feedback model for short term regulation of leukocyte integrins, involving sequential, integrin-dependent activation of the protein kinase C and adenylyl cyclase/cAMP-dependent kinase enzymatic pathways and leading to disengagement of the adhesion receptor from its specific ligand.
Rovere
P
P
Scientific Institute San Raffaele-DIBIT, Milan, Italy.
Inverardi
L
L
Bender
J R
JR
Pardi
R
R
D000199:Actins / Q000187:drug effects; D018821:CD18 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D000242:Cyclic AMP / Q000096:biosynthesis / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000276:immunology / Q000502:physiology*; D003599:Cytoskeleton / Q000187:drug effects; D015536:Down-Regulation / Q000276:immunology; D005246:Feedback / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014162:Transfection / Q000276:immunology
D000199:Actins; D018821:CD18 Antigens; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases