Selective up-regulation of phosphatidylinositol 3'-kinase activity in Th2 cells inhibits caspase-8 cleavage at the death-inducing complex: a mechanism for Th2 resistance from Fas-mediated apoptosis.
In this study the mechanism of differential sensitivity of CD3-activated Th1- and Th2-type cells to Fas-mediated apoptosis was explored. We show that the Fas-associated death domain protein (FADD)/caspase-8 pathway is differentially regulated by CD3 activation in the two subsets. The apoptosis resistance of activated Th2-type cells is due to an incomplete processing of caspase-8 at the death-inducing signaling complex (DISC) whereas recruitment of caspase-8 to the DISC of Th1- and Th2-like cells is comparable. Activation of phosphatidylinositol 3'-kinase upon ligation of CD3 in Th2-type cells blocked caspase-8 cleavage to its active fragments at the DISC, thereby preventing induction of apoptosis. This study offers a new pathway for phosphatidylinositol 3'-kinase in mediating protection from Fas-induced apoptosis.
Varadhachary
A S
AS
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Peter
M E
ME
Perdow
S N
SN
Krammer
P H
PH
Salgame
P
P
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002384:Catalysis; D002999:Clone Cells; D004789:Enzyme Activation / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D006868:Hydrolysis; D007113:Immunity, Innate / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000201:enzymology; D018418:Th2 Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*; D000077191:Wortmannin; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex; D002352:Carrier Proteins; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases; D004791:Enzyme Inhibitors; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077191:Wortmannin; D019014:fas Receptor; C506386:CFLAR protein, human; C505533:FADD protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human