Dendritic Cells Mediate Protective Immunity Against Salmonella Typhimurium by Regulating Antigen Presentation, Inflammation and Cell Death

Abstract

Salmonella enterica serovar Typhimurium (ST) is an intracellular bacterium that resides within the phagosome of infected cells. ST is the causative agent of gastroenteritis in humans and typhoid like disease in mice. ST infects epithelial cells and phagocytic cells such as dendritic cells (DCs), which are immune sentinels that have been regarded as the most critical antigen-presenting cell (APC). I evaluated the role of CD8α DCs, a subset of DCs capable of antigen presentation of phagosomal pathogens to activate CD8+ T cells. Furthermore, I assessed the role of key cytokines such as the group of classical anti-viral cytokines known as Interferon-I (IFN-I), on licensing CD8+ T cells. Interestingly, IFN-I signalling was necessary for production of inflammatory cytokines and induction of cell death, which activated CD8+ T cells and clearance of ST. Lastly, I examined the role of key cell death pathways in innate immune protection against ST. In particular, I addressed how signalling pathways in necroptosis and pyroptosis are critical for the production of IL-1beta and IL-18 which mediate immune protection against ST. Determining the mechanisms of which DCs engage innate and adaptive immune responses against phagosomal bacteria is the central question of my study and is addressed by examining critical roles of DC function, inflammation and cell death.