Memory CD8(+) T lymphocytes are critical effector cells of the adaptive immune system mediating long-lived pathogen-specific protective immunity. Three signals - antigen, costimulation and inflammation - orchestrate optimal CD8(+) T cell priming and differentiation into effector and memory cells and shape T cell functional fate and ability to protect against challenge infections. While amongst the conventional spleen dendritic cells (cDCs), the CD8α(+) but not the CD8α(-) cDCs, most efficiently mediate CD8(+) T cell priming, it is unclear which subset, irrespective of their capacity to process MHC-I associated antigens, is most efficient at inducing naïve CD8(+) T cell differentiation into pathogen-specific protective memory cells in vivo. Moreover, the origin of the required signals is still unclear. Using mice infected with the intracellular bacterium Listeria monocytogenes, we show that splenic CD8α(+) cDCs become endowed with all functional features to optimally prime protective memory CD8(+) T cells in vivo within only a few hours post-immunization. Such programming requires both cytosolic signals resulting from bacterial invasion of the host cells and extracellular inflammatory mediators. Thus, these data designate these cells as best candidate to facilitate development of cell-based vaccine therapy.