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, cir culating phenotype is a distinctive feature of mature leukocytes and i s thought to be essential for efficient immune surveillance, Leukocyte adhesion is a finely regulated process controlled in part by reversib le, activation-dependent up-regulation of beta(1)- and beta(2)-integri n function, To investigate the molecular basis of such reversibility i n human T lymphocytes, we developed a model of alpha L/beta(2) (LFA-1) -dependent adhesion that uses a heterologous cell line expressing huma n 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-base d cytoskeleton, thus dissociating LFA-1 from cytoskeletal anchoring pr oteins that normally connect the adhesion receptor to F-actin in lymph ocytes engaged in intercellular adhesion, Cells costimulated via the C D3 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-depe ndent adenylyl cyclase isoform, On the basis of these findings, we pro pose a feedback model for short term regulation of leukocyte integrins , involving sequential, integrin-dependent activation of the protein k inase C and adenylyl cyclase/cAMP-dependent kinase enzymatic pathways and leading to disengagement of the adhesion receptor from its specifi c ligand.