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 activated 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 ζ chain (CD3ζ ‐/‐ ) or the ITAM of the ζ chain (CD3ζ ‐/‐ :Tg ζ Δ67-150 ). Although the T cells from the CD3ζ ‐/‐ mice express extremely low levels of surface TCR, a subpopulation (~18%) of activated T cells could be induced to express TCR/FceRI g by using a powerful polyclonal activation protocol. These activated TCR/FceRI g T cells were capable of undergoing AICD, but its induction required 10 times as much anti-CD3e mAb as that required for AICD of wild-type T cells. Thus, the intensity of AICD correlated with the level of CD3 expression and was less efficient with activated, CD3ζ ζ ‐/‐ -derived T cells. By contrast, AICD of T cells from the CD3ζ ζ ‐/‐ :Tg ζ ζΔ Δ67-150 mice could be induced with low doses of anti-CD3e mAb and the extent of AICD was comparable to T cells from wild-type mice. The AICD induced in T cells from CD3ζ ‐/‐ , CD3ζ ζ ‐/‐ :Tg ζ ζΔ Δ67-150 and normal controls was specifically inhibited by Fas‐Ig fusion proteins. Our data support the ‘threshold model’ of AICD by demonstrating that AICD is controlled by the strength of T cell activation.