Feedback modulation of ligand-engaged αL/β2 leukocyte integrin (LFA-1) by cyclic AMP-dependent protein kinase

Patrizia Rovere, Luca Inverardi, Jeffrey R. Bender, Ruggero Pardi

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

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 β1- and β2-integrin function. To investigate the molecular basis of such reversibility in human T lymphocytes, we developed a model of αL/β2 (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.

Original languageEnglish (US)
Pages (from-to)2273-2279
Number of pages7
JournalJournal of Immunology
Volume156
Issue number6
StatePublished - Mar 15 1996

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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