ACTIVATION-INDUCED APOPTOSIS OF MATURE T-CELLS IS DEPENDENT UPON THE LEVEL OF SURFACE TCR BUT NOT ON THE PRESENCE OF THE CD3 ZETA-ITAM

Activation-induced cell death (AICD) occurs primarily in recently acti vated T cells after a second TCR triggering. Since a threshold in the activation status may be critical for AICD, it is likely that the CD3 ITAM, docking sites for tyrosine kinases, regulate AICD. A 'threshold model' for AICD was tested by using two targeted mutant mouse strains lacking either the zeta chain (CD3 zeta(-/-)) or the ITAM of the zeta chain (CD3 zeta(-/-):Tg(zeta Delta 67-150)). Although the T cells from the CD3 zeta(-/-) mice express extremely low levels of surface TCR, a subpopulation (similar to 18%) of activated T cells could be induced to express TCR/Fc epsilon RI gamma by using a powerful polyclonal acti vation protocol, These activated TCR/Fc epsilon RI gamma T cells were capable of undergoing AICD, but its induction required 10 times as muc h anti-CD3 epsilon mAb as that required for AICD of wild-type T cells. Thus, the intensity of AICD correlated with the level of CD3 expressi on and was less efficient with activated, CD3 zeta(-/-)-derived T cell s. By contrast, AICD of T cells from the CD3 zeta(-/-):Tg(zeta Delta 6 7-150) mice could be induced with low doses of anti-CDSE mAb and the e xtent of AICD was comparable to T cells from wild-type mice. The AICD induced in T cells from CD3 zeta(-/-), CD3 zeta(-/-):Tg(zeta Delta 67- 150) and normal controls was specifically inhibited by Fas-Ig fusion p roteins. Our data support the 'threshold model' of AICD by demonstrati ng that AICD is controlled by the strength of T cell activation.