Project 461529

We live in complex environments that expose us to potentially harmful agents. Infection, injury, and mutations resulting in cancerous cells all represent threats to our survival. Overcoming such threats requires that we possess the ability to sense danger and to respond in a way that neutralizes the threat. Our capacity to resist threats in this way is referred to as immunity and it is immune cells that serve as our danger sensors. One group of immune cells, called classical dendritic cells, are central to our ability to sense danger. They express receptors on their surface that detect molecular patterns associated with threats. The presence of danger initiates a series of events in the dendritic cells, referred to as inflammatory signalling, that culminate in an immune response. Sometimes, the molecular patterns are hidden in complex structures, like inside a cancer cell, and must be exposed. Dendritic cells can find hidden danger signals by ingesting material from around the body and digesting it to expose the hidden danger. Receptors inside the dendritic cells can then be engaged and an appropriate immune response can be initiated. Some of these receptors reside in a region of the dendritic cell called the cytosol, and their engagement is so critical to our immunity that when these pathways are impaired, we become dangerously vulnerable to infection and cancer. Despite its importance, the process by which danger signals from ingested material are delivered to intracellular danger receptors residing in the cytosol is not known. I have gathered evidence that a family of proteins known as apolipoproteins are critical to this process. This proposal will uncover how apolipoproteins orchestrate the ability of dendritic cells to sense danger and therefore to elicit immunity. Understanding this will allow us to design better immunotherapies for diseases that evade detection by dendritic cells, such as cancer.