Phosphatidylinositol 3-kinase participates in p56(lck)/CD4-dependent down-regulation of LFA-1-mediated T cell adhesion.
The mechanism inducing cell detachment in Ag-independent adhesion between lymphocytes is poorly understood. Different putative CD4 ligands, anti-CD4 Ab, a DR35-46 peptide mimicking residues 35 to 46 of HLA class II beta1, and a DR134-148 peptide mimicking residues 134 to 148 of HLA class II beta2, were previously found to down-regulate LFA-1-dependent adhesion between CD4+ T cells and HLA class II+ B cells. This down-regulation was shown to be p56(lck) dependent. Here we show that binding of these ligands to CD4 induced the activation of the tyrosine kinase p56(lck) associated with CD4 and also the lipid kinase phosphatidylinositol-3 kinase (PI3-kinase) associated with the CD4-p56(lck) complex in the HUT78 cell line. These events were not detected when p56(lck) was dissociated from CD4 in cell lines expressing mutated forms of CD4. It was also shown, using different inhibitors of the PI3-kinase (wortmannin, Ly294002, and antisense oligonucleotides), that this lipid kinase was necessary for the down-regulation of LFA-1-mediated adhesion induced by CD4 binding. These results strongly suggest that CD4-induced PI3-kinase activation, in the absence of concomitant TCR/CD3 triggering, leads to down-regulation of LFA-1-mediated T cell adhesion to B cells. The mechanism by which PI3-kinase could exert its effect remains unknown. Since PI3-kinase has previously been found to participate in the regulation of cytoskeleton structure, we propose that p56(lck)-associated PI3-kinase activation leads to a cytoskeleton organization unfavorable for LFA-1 function.
Mazerolles
F
F
INSERM Unit 429, Hôspital Necker-Enfants Malades, Paris, France.
Barbat
C
C
Hivroz
C
C
Fischer
A
A
D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D001483:Base Sequence; D015704:CD4 Antigens / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation; D004789:Enzyme Activation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D019061:src-Family Kinases / Q000378:metabolism*
D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D016169:Lymphocyte Function-Associated Antigen-1; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases