Immunological memory has been ascribed to the presence of long-lived memory cells. The mechanisms underlying their generation are not completely understood, but dependence on antigen persistence has been discussed in this regard. However, in spite of in vivo evidence favoring this model, studies on TCR/CD3 stimulation of T cell lines or unseparated peripheral blood T cell in vitro have failed to demonstrate prolonged survival of preactivated cells. We have examined the dose-dependent effect of TCR/CD3 engagement mimicked by immobilized anti-CD3 antibody. To this end, well-defined populations of CD4+ and CD8+ lymphoblasts isolated from bulk cultures of preactivated PBMCs by flow sorting were examined. These cells were restimulated with immobilized anti-CD3 in the presence or absence of various costimulatory factors, and were analyzed for their viability state, as well as their apoptotic and proliferative behavior. We have shown that inhibition of apoptosis following CD3 stimulation occurs at submitogenic concentrations, while activation-driven apoptosis requires high-density TCR/CD3 activation. Prevention of apoptosis by submitogenic CD3 stimulation was, however, observed only when CD4+ but not when CD8+ cells were investigated, and was not readily influenced by other costimulatory factors present in cultures. This observation points to the importance of antigen persistence in regulating survival of memory CD4+ but not CD8+ cells.