We have characterized parameters of both T cells and antigen-presenting cells (APCs) that influence high-dose suppression due to apoptosis. Blockade of interleukin-2 (IL-2) utilization is shown to inhibit both proliferation and the ensuing death. An analysis of sublines of a mature T cell clone demonstrates a correlation between IL-2 receptor alpha chain (IL-2R) induction, increased proliferation, and greater suppression at high antigen doses. Profound loss of cells at high antigen dose was found to require at least 48 to 72 hr to develop. Antigen add-back experiments showed that strong T cell receptor reengagement of activated, cycling cells was essential for proliferative suppression and cell loss. Increasing the ratio of APC:T lymphocytes to 50:1 augmented cell death. For antigen-induced death of lymph node T cells, fresh T-depleted splenocytes were more effective than splenocytes that had been irradiated or treated with mitomycin C. Thus, T lymphocyte apoptosis at high antigen doses is a function of the activation response of the T lymphocyte as well as the efficiency of antigen presentation by the APC. These results strengthen the theory that apoptosis takes part in a feedback regulatory mechanism that has been called propriocidal regulation, which limits T cell expansion at high antigen doses.