PERTUSSIS TOXIN INHIBITS ACTIVATION-INDUCED CELL-DEATH OF HUMAN THYMOCYTES, PRE-B LEUKEMIA-CELLS AND MONOCYTES

Activation of human thymocytes and pre-B cells via the CD3/T cell rece ptor (TCR) complex or the IgM/B cell receptor complex, respectively, r esults in apoptotic cell death. Similarly, crosslinking of the activat ion marker CD69, which belongs to the natural killer complex, causes a poptosis of lipopolysaccharide-preactivated monocytes. Here we show th at pertussis toxin (PTX) inhibits the activation-induced apoptosis of these three cell types, though it fails to prevent the programmed cell death that follows exposure of cells to the synthetic glucocorticoid dexamethasone (thymocytes, pre-B cells) or to interleukin 4 (monocytes ). The capacity of pertussis toxin to suppress activation-induced deat h is not due to quenching of the activation signal, because thymocytes exposed to PTX are still capable of mobilizing Ca2+ after TCR-alpha/b eta cross-linking and proliferate in response to costimulation with PT X and CD3/TCR ligation. The apoptosis-inhibitory effect of PTX depends on the presence of an intact adenosine diphosphate (ADP)-ribosylating moiety, since a mutant pertussis toxin molecule that lacks enzymatic activity, but still possesses the membrane translocating activity, fai ls to interfere with activation-induced cell death. A toxin that induc es a different spectrum of ADP ribosylation than PTX, cholera toxin, f ails to inhibit apoptosis. To suppress apoptosis, the intact PTX holot oxin must be added to cells before the lethal activation step; its add ition 30 min after initial activation remains without effect on apopto sis. These data unravel a PTX sensitive signal transduction event that intervenes during an early step of activation-induced cell death of i mmune cells.