The role of initiator caspases in post-activation T cell survival

Death receptors directly activate caspases through recruitment of the adapter protein FADD and caspase-8, which initiates apoptosis. Viral FLIP proteins (vFLIP) interfere with apoptosis signaling by death-domain containing receptors in the TNF-receptor superfamily. We show that T cell-specific transgenic expression of MC159 vFLIP inhibits Fas-induced apoptosis in thymocytes and peripheral T cells. However vFLIP expression also impairs post-activation survival of in vitro activated primary T cells in a cell-autonomous fashion in response to IL-2, IL-7 and IL-15. To determine the molecular mechanisms of this phenomenon, we have examined cytokine signal transduction and examined the effect of the vFLIP transgene and pharmacological caspase inhibitors on cytokine signal transduction and global gene expression profiling. We have identified a defect downstream of protein kinase B, upregulation of pro-apoptotic molecules, and dysregulation of cell cycle genes as hallmarks of caspase inhibition in activated T cells.