Abstract
We have previously shown that CD4 ligand binding inhibits LFA-1-dependent adhesion between CD4+ T cells and B cells in a p56(lck)- and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In this work, downstream events associated with adhesion inhibition have been investigated. By using HUT78 T cell lines, CD4 ligands were shown to induce a dissociation of LFA-1 from cytohesin, a cytoplasmic protein known to bind LFA-1 and to enhance the affinity/avidity of LFA-1 for its ligand ICAM-1. A dissociation of PI3-kinase from cytohesin is also observed. In parallel, we have found that CD4 ligand binding induced a redistribution of PI3-kinase and of the tyrosine phosphatase SHP-2 to the membrane and induced a transient formation of protein interactions including PI3-kinase; an adaptor protein, Gab2; SHP-2; and a SH2 domain-containing inositol phosphatase, SHIP. By using antisense oligonucleotides or transfection of transdominant mutants, down-regulation of adhesion was shown to require the Gab2/PI3-kinase association and the expression of SHIP and SHP-2. We therefore propose that CD4 ligands, by inducing these molecular associations, lead to sustained local high levels of D-3 phospholipids and possibly regulate the cytohesin/LFA-1 association.
Highlights
Leukocyte adhesion is a fundamental process in leukocyte physiology, which is strictly regulated and involves a number of interactions between different adhesion proteins [1]
Dissociation between PI3-kinase, LFA-1, and Cytohesin-1 Induced by CD4 T Cell Incubation with the HLA-DR -related 134 –148 Peptide—It has been previously shown by Kolanus et al [9] that LFA-1 in its active form is associated to an intracytoplasmic protein, cytohesin-1, expressing a pleckstrin homology (PH) domain to which the D-3 phospholipids synthesized by PI3-kinase could bind
We have investigated a hypothetic interaction between cytohesin-1 and PI3-kinase that could account for a local increase of D-3 phospholipids necessary to modify the 2 integrindependent adhesion
Summary
Leukocyte adhesion is a fundamental process in leukocyte physiology, which is strictly regulated and involves a number of interactions between different adhesion proteins [1]. By using antisense oligonucleotides or transfection of transdominant mutants, down-regulation of adhesion was shown to require the Gab2/PI3kinase association and the expression of SHIP and SHP-2. Potential interactions between PI3-kinase and LFA-1/cytohesin and the formation of protein association, including SHP-2, SHIP, or Gab2, induced by CD4 binding were investigated.
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