Mechanisms of antigen cross-presentation
Antigen cross-presentation is an immune process performed by dendritic cells (DCs) that is paramount for immunity against intracellular pathogens, viruses and cancer. Immunotherapies are promising therapeutic strategies that at least in part rely on eliciting cross-presentation. However, present formulations are in many cases poorly efficient, and this is perhaps in part because the intracellular mechanisms that govern cross-presentation are not fully understood. Phagocytosis of antigens renders their cross-presentation more efficient, and endoplasmic reticulum (ER) proteins are required, but the precise role that ER plays during cross-presentation has remained elusive. We identified a novel structure called membrane contact site, where the phagosomal and ER membranes are tightly juxtaposed, and which acts as a localized calcium signalling hub.
We found that DCs have a 5-fold higher frequency of these contacts than neutrophils, and that contact frequency correlated with cross-presentation efficiency. Our present research efforts are focused on exploring how contact sites may influence lipid transfer and intracellular trafficking to and from phagosomes to promote cross-presentation, using state of the art high resolution and functional imaging techniques. We aim not only to clarify how the ER participates in regulating cross-presentation, but also to identify novel pathways that may be exploited to improve cross-presentation efficiency in formulations of DC-based immunotherapies.