NF-kappa B signaling pathway governs TRAIL gene expression and human T-cell leukemia virus-I tax-induced T-cell death

The Tax oncoprotein encoded by human T-cell leukemia virus induces both T-c ell activation and apoptosis. The mechanism by which Tax induces apoptosis has remained unclear. Using genetically manipulated T-cell lines, we demons trate that Tax-induced T-cell death is dependent on NF-kappaB signaling. Ta x fails to induce apoptosis in T cells lacking I kappaB kinase gamma (IKK g amma), an essential component of the NF-kappaB signaling pathway. This defe ct was rescued when the mutant cells were reconstituted with exogenous IKK gamma. We further demonstrate that the Tax-induced T-cell death is mediated by TNF (tumor necrosis factor)-related apoptosis-inducing ligand (TRAIL), because this event can be effectively inhibited by a TRAIL-blocking antibod y. Consistent with this functional aspect, Tax stimulates the expression of TRAIL mRNA. Finally, we provide genetic evidence demonstrating that the NF -kappaB signaling pathway is essential for TRAIL gene induction by both Tax and T-cell activation signals. These studies reveal a novel function of th e NF-kappaB signaling pathway and suggest a key mechanism by which Tax indu ces T-cell death.