A blast from the past: clearance of apoptotic cells regulates immune responses

Key Points Apoptosis, a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes. However, the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by inducing or suppressing inflammation. Therefore, dead cells, which are a reflection of an organism's immediate past, can control its immunological future. Dying cells are recognized by phagocytes as being non-self, altered-self or non-motile self, using innate-immune recognition, scavenger receptors or immunoglobulin-superfamily molecules, respectively. Cell clearance by apoptosis has anti-inflammatory properties, by suppressing the release of pro-inflammatory cytokines by monocytes/macrophages and by the direct release of immunosuppressive cytokines, such as interleukin-10 and transforming growth factor-β1, by apoptotic cells. Dendritic-cell maturation and presentation of antigen are suppressed by the uptake of apoptotic cells, which leads to the promotion of tolerance. Defects in the clearance of apoptotic cells are associated with spontaneous/persistent tissue inflammation and autoimmunity to cell contents. Strategies to promote the safe, anti-inflammatory and immunosuppressive clearance of dying cells are discussed. There is a need to understand the mechanisms that, under certain circumstances, paradoxically allow apoptotic cells to stimulate the release of pro-inflammatory cytokines, such as tumour-necrosis factor, by macrophages and that allow dendritic cells to present antigen derived from apoptotic cells. Apoptosis, which is a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes. However, the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by enhancing or suppressing inflammation. Therefore, dead cells, which are a reflection of an organism's immediate past, can control its immunological future.