INDUCTION OF ACTIVATION-DRIVEN DEATH (APOPTOSIS) IN ACTIVATED BUT NOTRESTING PERIPHERAL-BLOOD T-CELLS

Signaling via the CD3/TCR complex induces programmed cell death (apopt osis) in immature thymocytes and transformed T lymphocytes (hybridomas or leukemic cells). Accumulating evidence indicates, however, that ap optosis can be triggered also in mature peripheral T cells. Here we sh ow that a significant fraction of cells of a given IL-2-dependent TCR- alphabeta+ clone or polyclonal short term line is killed when cultured for 20 h in the presence of PHA, anti-CD3 (OKT3), or anti-TCR (BMA031 ) mAb. Apoptosis can be triggered by these stimuli in CD4+, CD8+, and CD4-CD8- (double-negative) TCR-alphabeta+ clones. Activation-driven ce ll death (as quantified by propidium iodide staining and FACS analysis ) is associated with fragmentation of DNA into oligonucleosomal bands of approximately 200 bp. Although freshly isolated peripheral blood T cells are largely resistant to apoptosis, the sensitivity to anti-CD3/ TCR mAb or PHA-triggered cell death gradually increases upon activatio n and IL-2-dependent culture of T cells, and reaches a plateau level a fter 15 to 20 days. These data indicate that stimuli that activate res ting T cells initiate death by apoptosis in activated T cells. The imp lications of these results for the regulation of cellular immune respo nses and the establishment of peripheral tolerance will be discussed.