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Figure 1 Fas apoptotic signaling pathway. Binding of trimeric FasL to Its cognate receptor results in a coordinated cascade of cytoplasmic events leading to the activation of a series of cysteine proteases and ultimate death of the cell.

pro Caspasc 3 p32

Caspas® 3

PARP Cleavage Kirvijo AdlvatlCho Chromosomal DMA Dégradation

Figure 1 Fas apoptotic signaling pathway. Binding of trimeric FasL to Its cognate receptor results in a coordinated cascade of cytoplasmic events leading to the activation of a series of cysteine proteases and ultimate death of the cell.

of activation-induced cell death (AICD) whereby previously activated T cells that are stimulated through the TCR undergo apoptosis. In this regard, the process of AICD in T cell clones and hybridomas is blocked by antagonists of Fas. Moreover, lpr/lpr and gld/gld mice are deficient in AICD as a result of mutations in Fas and FasL, respectively, thereby demonstrating a pivotal role for Fas/FasL interactions in this process. Finally, Fas/FasL interactions have been demonstrated to mediate peripheral but not thymic deletion of antigen specific T cells in TCR transgenic mice.

Fas has also been implicated in regulating the duration of an immune response. Following a primary-immune response, the vast majority of lymphocytes are eliminated by apoptosis (clonal downsizing) and only a small percentage survive to differentiate into effector and memory cells. Fas appears to play a critical role in clonal downsizing because mice that are defective in the Fas/FasL (lpr/lpr and gld/gld mice) pathway accumulate lymphocytes over time, resulting in splenomegaly and lymphadenopathy (Figure 2).

As mentioned earlier, expression of Fas does not always correlate with susceptibility to Fas-induced apoptosis. Most naive T cells either express Fas or can be induced to express Fas rapidly upon activation, though these cells do not die upon signaling via Fas. Instead, ligation of Fas on these T cells in the presence of T cell receptor cross-linking results in enhanced proliferation, increased expression of activation markers and increased cytokine production. Signaling via Fas in other cells, such as certain B cell lines and the HT-29 colon carcinoma cell line, can also result in activation and cytokine secretion rather than apoptosis. Upon continued stimulation, however, T cells become progressively susceptible to induction of apoptosis subsequent to cross-linking of Fas by either multimeric Fas-specific antibodies or FasL. Thus, the activation state of the cell appears to be a crucial determinant of whether h Tea

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