The NF-kappa B signaling pathway is not required for Fas ligand gene induction but mediates protection from activation-induced cell death

Stimulation of T cells by antigens or mitogens triggers multiple signaling pathways leading to activation of genes encoding interleukin-2 and other gr owth-regulatory cytokines. The same stimuli also activate the gene encoding an apoptosis-inducing molecule, Fas ligand (FasL), which contributes to ac tivation-induced cell death. It has been proposed that the signaling pathwa ys involved in cytokine gene induction also contribute to activation-induce d Fast expression; however, genetic evidence for this proposal is lacking. In the present study, the role of the NF-kappa B signaling pathway in Fast gene expression was examined using a mutant T cell line deficient in an ess ential NF-kappa B signaling component, I kappa B kinase gamma, These mutant cells have a blockade in signal-induced activation of NF-kappa B but remai ned normal in the activation of NF-AT and AP-1 transcription factors. Inter estingly, the NF-kappa B signaling defect has no effect on mitogen-stimulat ed Fast gene expression, although it completely blocks the interleukin-2 ge ne induction. We further demonstrate that NF-kappa B activation is required for protecting T cells from apoptosis induction by mitogens and an agonist ic anti-Fas antibody. These genetic results suggest that the NF-kappa B sig naling pathway is not required for activation-induced Fast expression but r ather mediates cell growth and protection from activation-induced cell deat h.