Dendritic cells (DC) are professional antigen presenting cells that are critical in the regulation of both innate and adaptive immune responses. DEC205 is the major endocytic receptor expressed on DCs, where it is responsible for internalizing extracellular-derived antigens for presentation to the immune system. Accordingly, DEC-205 constitutes one of the most widely used therapeutic targets for vaccine delivery. Here we demonstrate that DEC-205 undergoes a pH-dependent change in oligomeric status that correlates with its capacity to recognize ligands associated with cellular death. Using cryo-electron microscopy, we determined the structure of DEC-205 at acidic and basic pH to an overall resolution of 3.2A and 4.9A respectively. In an acidic environment, DEC-205 formed a compact monomer with an overall structure resembling that of a leminscate (infinity symbol). This architecture was underpinned by the CTLD5 domain, which possessed a distended loop that is implicated as a pH labile inter-domain recruitment hub. Under basic conditions, DEC-205 underwent a structural reorganization that triggered the formation of a toroid-shaped tetramer. Notably, a Histidine residue previously implicated in keratin binding is buried upon DEC-205 oligomerisation, thereby providing a mechanistic basis for the pH-dependent recognition of apoptotic and necrotic cells by DEC-205. Overall, these data suggest that DEC-205 self-association functions as a ‘safety switch’ to allow antigen recognition only within the context of cellular death.