The immune system has developed a number of mechation and have used a retrovirus-based gene transfer nisms to eliminate cells that are harmful to the body, system to constitutively express c-FLIP in lymphocytes. including lymphocytes that respond to self-antigens and cells that are infected with viruses or other intracellular pathogens. The best understood of these involves the Results and Discussion death receptor, Fas, a member of the tumor necrosis factor (TNF) receptor superfamily (Nagata, 1997). Similar c-FLIP Is Downregulated following Lymphocyte Activation to other members of this protein family, engagement of Fas by its ligand, FasL, results in the recruitment of the Recently, a number of studies have suggested that the level of c-FLIP in T cells determines their sensitivity to aspartate-specific cysteine protease precursor, procaspase 8, leading to the activation of a caspase cascade death receptor–mediated apoptosis (Irmler et al, 1997; Refaeli et al., 1998). We therefore wanted to examine and the induction of apoptosis (Boldin et al., 1996; Muzio et al., 1996). The physiological importance of this death the levels of c-FLIP in B and T lymphocytes both before and after activation. Naive T cells express high levels receptor is illustrated by the phenotype of mice that lack a functional fas gene. Thesemicedevelopsystemic of c-FLIP but lose expression of the protein and its mRNA and become sensitive to Fas-mediated apoptosis autoimmunity characterized by an accumulation of lymphocytes and the production of multiple autoantibodies when they are activated with their cognate peptide or anti-CD3 (Figure 1; data not shown; Irmler et al., 1997;(Adachi et al., 1995; Nagata and Suda, 1995). Notably, Fas deficiencies in humans have recently been associ- Refaeli et al., 1998). Similarly, naive B cells become sensitive to Fas-mediated apoptosis and lose c-FLIP ated with an autoimmune lymphoproliferative syndrome expression after they are activated with anti-CD40 (Figure 1; data not shown). Thus, in vitro activation of lym-