The elimination of activated but not resting T cells involves apoptosis induced either by restimulation via the TCR/CD3 complex, CD2, or by signaling through the Fas Ag. The factors regulating the shift of an apoptosis-resistant to an apoptosis-sensitive phenotype and vice versa have not so far been clarified. Here we report that TGF-beta 1, when present during a PHA activation course, significantly increases viability of human T cells upon reculture in medium alone, following restimulation via CD2, CD3, or after triggering the Fas Ag. Using DNA gel electrophoresis and an in situ nick translation technique we further show that activation-induced and Fas-mediated apoptosis are reduced in T cells that were prestimulated with PHA plus TGF-beta 1, compared with control cells prestimulated with PHA alone. Moreover, when PHA-preactivated T cells are further expanded in IL-2, inclusion of TGF-beta 1 results in higher cell yields at any timepoint from day 30 to 75 of cell culture compared with control cultures without TGF-beta 1. However, no differences in Fas or bcl-2 protein expression are found between cells stimulated in the absence or presence of TGF-beta 1. Together, our data identify TGF-beta 1, when present during an activation course, as an important viability factor possibly of importance for the generation of effector and/or long-lived memory T cells.