BCL-2 AND FAS APO-1 REGULATE DISTINCT PATHWAYS TO LYMPHOCYTE APOPTOSIS/

Activation of the cell surface receptor Fas/APO-1 (CD95) induces apopt osis in lymphocytes and regulates immune responses. The cytoplasmic me mbrane protein Bcl-2 inhibits lymphocyte killing by diverse cytotoxic agents, but we found it provided little protection against Fas/APO-1-t ransduced apoptosis in B lymphoid cell lines, thymocytes and activated T cells. In contrast, the cowpox virus protease inhibitor CrmA blocke d Fas/APO-1-transduced apoptosis, but did not affect cell death induce d by gamma-radiation or serum deprivation. Signalling through Fas/APO- 1 did not down-regulate Bcl-2 or induce its antagonists Bar and Bcl-x( S). In Fas/APO-1-deficient lpr mice, Bcl-2 transgenes markedly augment ed the survival of antigen-activated T cells and the abnormal accumula tion of lymphocytes (although they did not interfere with deletion of autoreactive cells in the thymus). These data raise the possibility th at Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apopto sis.