Dendritic cells (DC) were found to down-regulate Bcl-2 protein upon maturation in vivo. Because Bcl-2 has been shown to exert anti-apoptotic functions, down-regulation of Bcl-2 could be a mechanism by which DC longevity is controlled. To dysregulate this potential control system and to study the role of Bcl-2 in DC, we expressed human Bcl-2 under control of the murine CD11c-promoter as a transgene specifically in DC and show that DC frequencies and numbers increase in transgenic mice. In vivo bromodeoxyuridin, as well as adoptive, DC transfer studies show that the relative turnover/survival of mature Bcl-2 transgenic DC is increased. This had a direct impact on CD4+ T cell, as well as humoral immune, responses, which were elevated in transgenic animals. When Bcl-2 transgenic DC were used as DC vaccines, they induced 2-to 3-fold greater expansion of Ag-specific CTL, and stronger in vivo cytotoxicity. Overall, these data indicate that down-regulation of Bcl-2 controls DC longevity, which in turn directly regulates immune responses and the efficacy of DC when used as vaccines.