APOPTOSIS SIGNALING PATHWAYS IN NORMAL T-CELLS DIFFERENTIAL ACTIVITY OF BCL-2 AND IL-1-BETA-CONVERTING ENZYME FAMILY PROTEASE INHIBITORS ONGLUCOCORTICOID-MEDIATED AND FAS-MEDIATED CYTOTOXICITY

Fas-mediated apoptosis plays an important role in regulating the immun e response in peripheral T cells. Restimulation of T cell blasts up-re gulates Fas and Fas ligand expression, with subsequent interaction lea ding to cell death. Overexpression of Bcl-2 in tumor cells blocks apop tosis induced by many stimuli, but inhibition of Fas-mediated killing has not been consistently observed. To examine the behavior of Bcl-2 i n normal cells, T cell blasts were transiently transfected with Bcl-2 and related gene products to determine the effect on apoptotic signali ng. Transient overexpression of Bcl-2 in mouse and human T cell blasts did not block Fas-mediated apoptosis, whereas etoposide- and glucocor ticoid-induced cytotoxicity was potently inhibited, Expression of Bcl- x(L) and adenovirus E1B 19K did not interfere with anti-fas killing. I n contrast, interleukin-1 beta-converting enzyme family protease inhib itors Ac-DEVD-CHO and CrmA blocked Fas-mediated apoptosis. These resul ts suggest that peripheral T cells use distinct apoptosis signaling pa thways with differential sensitivity to Bcl-2 and interleukin-1 beta-c onverting enzyme family protease inhibitors. Since T cells normally ex press Bcl-2 and Bcl-x(L) following activation, their inability to bloc k Fas-mediated apoptosis may allow for the elimination of self-reactiv e cells and the appropriate regulation of immune responses.