Enhanced basal AP-1 activity and de-regulation of numerous genes in T cells transgenic for a dominant interfering mutant of FADD/MORT1.

The essential role of FADD/MORT1 and caspase-8 in 'death-receptor'-induced apoptosis is well characterized. Surprisingly, these proteins also play a critical role in antigen- or mitogen-induced activation and proliferation of T cells. We report the results of gene expression profiling in T cells from mice defective in FADD-signaling due to transgenic expression of a dominant negative mutant of FADD (FADDdn T cells). Of the tested genes, 159 were differentially expressed in mutant cells prior to or, more often, after mitogenic stimulation for 20 h. No obvious regulator of proliferation was changed in expression. However, a number of T cell effector genes such as IL-2 and IL-9 were up-regulated upon stimulation. Analysis of IL-2 regulation showed enhanced mRNA induction but normal protein production in activated FADDdn T cells. Activation of the nuclear factor of activated T cells was normal upon stimulation but the activity of the activator protein 1 (AP-1) family was strongly increased in resting FADDdn T cells. Expression and transcriptional activity of classical AP-1 family members was unaltered in FADDdn cells, suggesting the involvement of other AP-1 family members. The constitutive activation of AP-1 may thus serve to precondition resting T cells for an enhanced expression of many immunologically relevant genes during activation.