BCL-2 COUNTERS APOPTOSIS BY BAX HETERODIMERIZATION-DEPENDENT AND HETERODIMERIZATION-INDEPENDENT MECHANISMS IN THE T-CELL LINEAGE

The effect of the cell death inhibitor Bcl-2 in relation to its capaci ty to dimerize with apoptosis promoter Bar or its homologs at their ph ysiological expression levels was explored in the T-cell lineage. Tran sgenic mice expressing a BH1 mutant Bcl-2 (Bcl-2 mI-3), which fails to heterodimerize with proapoptotic members of the Bcl-2 family, such as Bar, were generated. Bcl-2 mI-3 protected immature CD4(+)8(+) thymocy tes from spontaneous, glucocorticoid and anti-CD3-induced apoptosis an d altered T cell maturation, resulting in increased percentages of CD3 (hi) and CD4(-)8(+) thymocytes. In contrast, apoptosis of peripheral T -cells was unaffected by transgene expression. This correlated with th eir high Bar expression level and insensitivity to the caspase inhibit or, zVAD-fmk, a functional hallmark of Bax-like activity. Thus, within the T-cell lineage Bcl-2 can inhibit apo ptosis independent of its as sociation with Bar or its homologs; yet, above a threshold level of th eir physiologic proapoptotic activity, the capacity of Bcl-2 to hetero dimerize with Bax or its homologs appears essential for it to counter cell death.