The relevance of direct inflammatory signals (signal 3) for the activation of memory CD8+ T cells during recall responses is so far unknown. We therefore investigated the direct impact of IL-12 and type I IFN on the formation, recall potential and protective capacity of memory T cells. Using CD8+ T cells deficient for IL-12 or type I IFN receptors in an adoptive transfer system, we generated memory populations after infection with vaccinia virus, lymphocytic choriomeningitis virus or Listeria monocytogenes. The results demonstrate that in the absence of signal 3 cytokines during primary infection, functional memory T cells were formed. After retransfer into naïve mice, signal 3-deficient memory T cells were able to specifically lyse target cells in vivo under non-infectious conditions. However, after reinfection, secondary effector CD8+ T cells lacking signal 3 were impaired in expansion and protective capacity dependent on the nature of the pathogen. We conclude that memory CD8+ T cells depend on a signal 3 for expansion, independent of signals obtained during priming, thereby being influenced by the pathogen-induced inflammatory milieu during secondary infection. In summary, our results reveal an essential role for direct inflammatory cytokine signaling in secondary T-cell responses.