Molecular events associated with CD4-mediated Down-regulation of LFA-1-dependent adhesion.
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.
Mazerolles
Fabienne
F
INSERM U 429, Bat. Kirmisson, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France. mazerol@necker.fr
Barbat
Christiane
C
Trucy
Maylis
M
Kolanus
Waldemar
W
Fischer
Alain
A
D015704:CD4 Antigens / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D018613:Microscopy, Confocal; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D013601:T-Lymphocytes / Q000378:metabolism
D015704:CD4 Antigens; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases