Inhibition of caspase or FADD function blocks proliferation but not MAP kinase-activation and interleukin-2-production during primary stimulation of T cells.
Caspases are instrumental in the implementation of apoptotic cell death, and caspase activation is in most investigated cases closely linked to apoptosis. Recent data demonstrate, however, that caspases are also activated during primary T cell activation in the absence of apoptosis. Here we provide evidence that caspase activity is required for some but not all aspects of T cell activation. CD3-triggered proliferation of mouse T cells was impaired in the presence of the pan-caspase-inhibitor Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk) and the number of cells entering the cell cycle was reduced. Costimulation by CD28 or externally added interleukin-2 (IL-2) failed to rescue proliferation. Re-stimulation of pre-activated T cells, however, was not affected by Z-VAD-fmk. Intriguingly, CD3-induced production of IL-2 by primary T cells was not impaired in the presence of Z-VAD-fmk. Likewise, CD3-induced activation of mitogen-activated protein kinases was unaffected by Z-VAD-fmk and intracellular levels of inhibitory kappaBalpha were the same as in control cells. T cells transgenically expressing a dominant negative mutant of the caspase-adaptor Fas-associated molecule with death domain (FADD)/MORT1 displayed the same pattern of reaction, i.e. a reduced proliferative response but normal IL-2-production. These data show a distinct role of caspases during primaryT cell activation and provide evidence for a FADD-caspase-pathway not only in the induction of apoptosis but also of T cell proliferation.
Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany.
Astrid
A
Mack
Georg
G
Häcker
D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017252:CD3 Complex / Q000276:immunology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000494:pharmacology; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D000590:Amino Acid Chloromethyl Ketones; D017252:CD3 Complex; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D007376:Interleukin-2; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases