Bloodstream infections induce considerable morbidity， high mortality， and represent a significant burden of cost in health care; however， our understanding of the immune response to bacteremia is incomplete. Langerin CD8α dendritic cells (DCs)， residing in the marginal zone of the murine spleen， have the capacity to cross-prime CD8 T cells and produce IL-12， both of which are important components of antimicrobial immunity. Accordingly， we hypothesized that this DC subset may be a key promoter of adaptive immune responses to blood-borne bacterial infections. Utilizing mice that express the diphtheria toxin receptor under control of the langerin promoter， we investigated the impact of depleting langerin CD8α DCs in a murine model of intravenous infection with bacille Calmette-Guerin (BCG). In the absence of langerin CD8α DCs， the immune response to blood-borne BCG infection was diminished: bacterial numbers in the spleen increased， serum IL-12p40 decreased， and delayed CD8 T cell activation， proliferation， and IFN-γ production was evident. Our data revealed that langerin CD8α DCs play a pivotal role in initiating CD8 T cell responses and IL-12 production in response to bacteremia and may influence the early control of systemic bacterial infections.