Cell death in the maintenance and abrogation of tolerance: the five Ws of dying cells

The mammalian immune system continually faces death in the form of its own dead and dying cells that arise during normal tissue turnover, infections, cellular damage, and cancer. Complex decisions must then be made that will permit a protective response to pathogens, while at the same time destroying tumors but not attacking vital systems of the host that could lead to autoimmunity. By using an investigative technique termed the five Ws (who, what, when, where, and why), we will examine how the immune system responds to antigens generated via cell death. This analysis will give us a better understanding of the molecular differences fundamental to tolerogenic or immunogenic cell death, the cells that sense and react to the dead cells, and the consequences of these fundamental elements on the maintenance or abrogation of tolerance.