Cross-linking the TCR in T cell hybridomas induces cell apoptosis following activation. This activation-induced apoptosis has been used as a model for clonal deletion of thymocytes or peripheral T cells. Anti-TCR-induced apoptosis of T cell hybridomas requires de novo macromolecular synthesis, including up-regulation of Fas and FasL. The Fas-FasL interaction then activates the apoptosis program. To study apoptosis-specific signaling processes, we generated a mutant T cell hybridoma line defective in induction of apoptosis, but competent to induce activation, upon TCR triggering. Subsequently, we cloned the gene TDAG51, which restored activation-induced apoptosis when transfected into the mutant cell line, and showed that TDAG51 expression was required for Fas expression. Thus, TDAG51 plays an essential role in induction of apoptosis by coupling TCR stimulation to Fas expression.