Effects of a dominant interfering mutant of FADD on signal transduction inactivated T cells

The cytoplasmic adaptor protein FADD is an essential component of the death -inducing signaling complexes (DISCs) that assemble when TNF receptor famil y members, such as Fas, are ligated, FADD inititates the proteolytic cascad e that leads to apoptosis by binding to and promoting the autocatalytic act ivation of caspase-8 [1-4], Surprisingly, FADD (but not caspase-8) is also required for T cells to proliferate upon their stimulation with mitogens [5 -9]. Using transgenic mice expressing a dominant-negative mutant of FADD (F ADD-DN), we show that functional FADD is required for T cells to proliferat e in response to antigens in vivo as well as to mitogens in culture. The co stimulation of wild-type and FADD-DN T cells with mitogens revealed that FA DD-DN T cells have a cell-autonomous defect in intracellular signaling. In contrast to another study [6], p53 deficiency did not rescue mitogen-induce d proliferation of FADD-DN T cells, and neither did enforced expression of the apoptosis inhibitor Bcl-2, Like wild-type T cells, FADD-DN T cells stim ulated with mitogens mobilized intracellular calcium and activated members of the UP-KS transcription factor family as well as p38 mitogen-activated p rotein kinase (MAPK) and p44/42 MAPK, Therefore, FADD must act downstream o f or in parallel to these signaling pathways.