ROLE OF ANTIGEN, CD8, AND CYTOTOXIC T-LYMPHOCYTE (CTL) AVIDITY IN HIGH-DOSE ANTIGEN INDUCTION OF APOPTOSIS OF EFFECTOR CTL

Experimental data suggest that negative selection of thymocytes call o ccur as a result of supraoptimal antigenic stimulation. It is unknown, however, whether such mechanisms are at work in mature CD8(+) T lymph ocytes. Here, we show that CD8(+) effector cytotoxic T lymphocytes (CT L) are susceptible to proliferative inhibition by high dose peptide an tigen, leading to apoptotic death mediated by TNF-alpha release. Such inhibition is not reflected in the cytolytic potential of the CTL, sin ce concentrations of antigen that are inhibitory for proliferation pro mote efficient lysis of:target cells. Thus, although CTL have committe d to the apoptotic pathway, the kinetics of this process are such that CTL function can occur before death of the CTL. The concentration of antigen required for inhibition is a function of the CTL avidity, in t hat concentrations of antigen capable of completely inhibiting high av idity CTL maximally stimulate low avidity CTL. Importantly, tile inhib ition call be detected in both activated and resting CTL. Blocking stu dies demonstrate that the CD8 molecule contributes significantly to th e inhibitory signal as the addition of anti-CD8 antibody restores the proliferative response. Thus, our data support the model that mature C D8(+) CTL can accommodate an activation signal of restricted intensity , which, if surpassed, results in deletion of that cell.