Abstract Fully functional CD8+ T cell memory is highly dependent upon CD4+ T cell support. CD4+ T cells play a critical role in inducing the expression of CD70, the ligand for CD27, on dendritic cells. In this study, we demonstrate that CD27 stimulation during primary CD8+ T cell responses regulates the ability to mount secondary CD8+ T cell responses. CD27 stimulation during vaccinia and dendritic cell immunization controls the expression of the IL-7R (CD127), which has been shown to be necessary for memory CD8+ T cell survival. Furthermore, CD27 stimulation during primary CD8+ T cell responses to vaccinia virus restrained the late expression on memory precursor cells of cytokine receptors that support terminal differentiation. The formation of CD8+ T cell memory precursors and secondary CD8+ T cell responses was restored in the absence of CD27 costimulation when endogenous IL-12 was not available. Similarly, the lesion in CD8+ T cell memory that occurs in the absence of CD4+ T cells did not occur in mice lacking IL-12. These data indicate that CD4+ T cell help and, by extension, CD27 stimulation support CD8+ T cell memory by modulating the expression of cytokine receptors that influence the differentiation and survival of memory CD8+ T cells.