Membraneassociated Proteins

More recently, it was shown that cells from perforin deficient mice could still reject tumors, and that in double knock out mice for IFN-g and peforin, control of tumor can be hampered by administration of anti-TNF antibody [73, 74]. These data imply that other mechanisms, that do not necessitate perforin activity, can be involved in CTL-induced cell damage. And indeed, Fas ligand that is present on the cytoplasmic membrane of activated CD8 T cells can bind to FAS on target cells and lead to apoptotic cell death. Fas (APO-1/CD95) is a member of the TNF-R family involved in mediating death signals [75]. It is a type I transmembrane receptor widely expressed in human tissues. Upon binding of FAS to its specific ligand in a trimeric configuration, a series of signals lead to formation of active death-inducing signaling complex (DISC). Caspase-8-mediated activation of Caspase-3, following activation mediated by caspase-8, kills cells through cleavage and destruction of multiple cellular target structures [76]. Fas ligand is another TNF-related transmembrane molecule; under physiological conditions, its expression is confined to a limited spectrum of cell types, in particular to activated T cells [77]. Although the direction of signal transduction is usually from ligand to receptor, reverse signaling may occur between partner activated T cells, and modulate the immune reaction. FasL-mediated signaling was recently shown to act as CD28-independent T cells costim-ulation that synergizes with TCR-specific stimulation to enhance IFN-g- production [78]. Following antigen contact and under the influence of IL-2, CTLs upregulate FasL, increasing target cell killing while resisting Fas-induced apoptosis.

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