Cell Death Trigger Defines Differential Immune Responses from Self-tolerance to Inflammation

The mammalian immune system must respond to millions of cells that die in the body each day as result of normal cell turnover, infection, exposure to cytotoxic substances, trauma, and other factors. Depending on the context and death trigger, cells undergo different death processes, including apoptosis and necrosis. These dying or dead cells are swiftly recognized and phagocytosed by immune cells including macrophages and dendritic cells. The mechanisms by which these cells are recognized and internalized are still not fully understood. Furthermore these mechanisms appear to depend on what mode of cell death has occurred. In this study, the immune responses of macrophages to cells killed using different death triggers were analyzed. Jurkat T cells were killed via apoptosis using two chemotherapy agents, actinomycin D and etoposide. It was observed that actinomycin D-killed cells suppress the immune response in macrophages and block the secretion of pro-inflammatory cytokines, whereas etoposide-killed cells do not. Further characterization of actinomycin D-killed cells showed that actinomycin D, and not the apoptotic cells, was responsible for the immunosuppression of the immune system. In addition, it was observed that necrotic cells were not sufficient on their own to simulate the secretion of pro-inflammatory cytokines. However, Jurkat T cells killed by 55oC treatment, but not freeze-thaw, had a synergistic effect on LPS-stimulated macrophages. This study underscores the importance of understanding the mechanisms that underlie how different cell death stimuli impact and regulate immunological outcomes, especially when these cells are being used in surrogate in vitro systems to study in vivo phenomena