Regulation of Fas and FasL expression during activation-induced T cell apoptosis

Activation-induced cell death (AICD) in T cells plays a critical role in immune tolerance and lymphocyte homeostasis. AICD often proceeds via the signals induced by Fns (CD95/APO-1)/Fas ligand (FasL/CD95L) interactions. which elicit the activation of a cascade of caspases in a transcription-independent manner. The expression of Fas and FasL is one of the final checkpoints determining the fate of activated T lymphocytes. Whits there have been extensive studies on Fas/FasL-induced execution machinery, our research has focused on the molecular mechanisms regulating Fas and FasL expression. Our previous results have shown that activation of T-cell hybridomas lends to AICD. a process completely dependent on Fas and Fast. Subsequent to our previous report of the requirement for protooncoprotein c-myc in activation-induced apoptosis, we found that the c-myc effect is exerted through the regulation of Fast expression. Moreover, the expression of Fast requires both PKC activation and Ca++ influx. Additionally. ii appears to be restricted to a particular phase of the cell cycle. and is modulated by the activity of the c-myc pathway. In contrast. Fas expression is independent of c-myc. and is regulated by the: activity of PKC alone. probably through p53 and transcription factor TDAG51 Since Fas/FasL-mediated cell death has also been implicated in tumor immunity. neuronal degeneration. and AIDS. Further elucidation of the regulation of Fas/FasL expression may facilitate improved management and prognosis of these diseases.