CD4 ligation induces activation of protein kinase C zeta and phosphoinositide-dependent-protein kinase-1, two kinases required for down-regulation of LFA-1-mediated adhesion.
We previously showed that CD4 binding induced a down-regulation of LFA-1-dependent-antigen-independent adhesion of T and B lymphocytes in a phosphatidylinositol-3-kinase (PI3K)-dependent manner. We now show in A201-CD4 (+) T cell lines, that anti-CD4 Ab increases activation of phosphoinositide-dependent-protein-kinase 1 (PDK1) or PKC zeta, two main effectors down-stream from PI3K. CD4 binding also increases interactions between PI3K and activated PKCzeta and PDK1. Both events are dependent on CD4/p56Lck association, since they are not detected when p56Lck is unable to bind a truncated form of CD4 in transfected T cell lines. We also show using antisense oligonucleotides that both kinases are necessary for down-regulating LFA-1-dependent adhesion induced by CD4 signalling. We also suggest a role of PDK1 in the recruitment of the phosphatase SHP-2 in a multiprotein complex induced by anti-CD4 Ab. This study thus provides further insights into the mechanism underlying the CD4 triggered regulation of LFA-1-mediated adhesion.
Trucy
Maÿlis
M
INSERM, U768, 75015, Site Necker, 147 rue de sevres Paris, F-75015 Paris, France.
Barbat
Christiane
C
Fischer
Alain
A
Mazerolles
Fabienne
F
D064413:3-Phosphoinositide-Dependent Protein Kinases; D001402:B-Lymphocytes / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation; D004789:Enzyme Activation / Q000502:physiology*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D064413:3-Phosphoinositide-Dependent Protein Kinases; D015704:CD4 Antigens; D016169:Lymphocyte Function-Associated Antigen-1; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D000099221:Protein Kinase C zeta; C578562:PDPK1 protein, human