The mechanisms responsible for the down-modulation of the activation of separated CD4+ or CD8+ human T cell blasts were studied using cells obtained from healthy donors. In the absence of IL-2, human CD4+ T cell blasts were sensitive to both FasL and Apo2L/TRAIL, but human CD8+ T cell blasts died, with no additional effect of death receptor ligation. CD8+ T cell blasts were more sensitive than CD4+ T cell blasts to apoptosis induction by IL-2 deprivation, which was associated with a decrease in the expression of anti-apoptotic proteins of the Bcl-2 family, especially of Mcl-1 in CD8+ T cell blasts. The maintenance of high levels of Bim expression was also necessary, since down-modulation of Bim expression by siRNA in normal human CD8+ T cell blasts greatly reduced apoptosis by IL-2 deprivation. These data, together with previous works, point to an important role of the presence or absence of immuno-stimulatory cytokines in the type of regulation of human CD8+ T cell responses (death by cytokine deprivation versus death receptor inhibition of cytokine-dependent growth).