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.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health grants AI077565 (T.S.G.), CA109446 (T.S.G.), EY06765 (T.A.F.), EY015570 (T.A.F.), and EY02687 (Department of Ophthalmology and Visual Science Core Grant, Washington University, St. Louis, MO). Additional support was obtained from a University of Iowa Carver College of Medicine Medical Research Initiative Grant (T.S.G.) and a Department of Ophthalmology and Visual Science grant from Research to Prevent Blindness (New York, NY) (T.A.F.) and the Macular Vision Research Foundation (West Conshohocken, PA) (T.A.F.). The authors wish to express their sincere thanks to J. Choi and P. Gurung for designing the figures.