The immune system encounters dead cells during normal cell turnover, injury, and infection. It must distinguish between different forms of cell death to eliminate pathogens, promote healing, and avoid autoimmune responses. However, eliminating tumors often requires an immune response against host tissue. Thus, understanding how the immune system determines whether cell death is immunogenic, tolerogenic, or silent is a central problem in immunology. Cell death can be immunogenic or tolerogenic depending on the type of death and the signals released. Apoptosis, a form of programmed cell death, is typically considered tolerogenic, while necrosis is immunogenic. However, recent studies show that certain apoptotic cells can be immunogenic, and that the composition of cell surface molecules and secreted products, including damage-associated molecular patterns (DAMPs), can influence immunogenicity. DAMPs are released from dying cells and can induce immune responses to cellular antigens. For example, HMGB1, a DNA-binding protein, can be released during apoptosis and promote immune responses. Similarly, calreticulin (CRT) is exposed on the surface of dying cells and can enhance immunogenicity. However, the presence of certain factors, such as caspase activation, can modify DAMPs and reduce immunogenicity. The engulfment of dying cells by antigen-presenting cells (APCs) such as dendritic cells (DCs) can influence immune responses. The type of DC and the signals it receives from the dying cell determine whether the immune response is immunogenic or tolerogenic. For example, CD8α⁺ DCs are more likely to induce tolerance, while CD8α⁻ DCs promote immunity. The location of dying cells and the cells that engulf them also plays a role in determining the immune response. For instance, intravenous injection of apoptotic cells can induce tolerance in the spleen, while subcutaneous injection can induce immunity. The spleen appears to be an organ of tolerance, while lymph nodes are more involved in immune responses. Receptors on phagocytes that recognize dying cells, such as MFG-E8 and Tim-4, can influence the immune response. The modification of DAMPs during apoptosis can also affect immunogenicity. For example, caspase activation can lead to the release of HMGB1, which can promote immunity, while the absence of caspase activation can reduce immunogenicity. The immune system's response to dying cells is complex and influenced by various factors, including the type of cell death, the signals released, the type of APC, and the location of the dying cells. Understanding these factors is crucial for developing strategies to enhance immune responses against tumors and pathogens while avoiding autoimmune reactions.The immune system encounters dead cells during normal cell turnover, injury, and infection. It must distinguish between different forms of cell death to eliminate pathogens, promote healing, and avoid autoimmune responses. However, eliminating tumors often requires an immune response against host tissue. Thus, understanding how the immune system determines whether cell death is immunogenic, tolerogenic, or silent is a central problem in immunology. Cell death can be immunogenic or tolerogenic depending on the type of death and the signals released. Apoptosis, a form of programmed cell death, is typically considered tolerogenic, while necrosis is immunogenic. However, recent studies show that certain apoptotic cells can be immunogenic, and that the composition of cell surface molecules and secreted products, including damage-associated molecular patterns (DAMPs), can influence immunogenicity. DAMPs are released from dying cells and can induce immune responses to cellular antigens. For example, HMGB1, a DNA-binding protein, can be released during apoptosis and promote immune responses. Similarly, calreticulin (CRT) is exposed on the surface of dying cells and can enhance immunogenicity. However, the presence of certain factors, such as caspase activation, can modify DAMPs and reduce immunogenicity. The engulfment of dying cells by antigen-presenting cells (APCs) such as dendritic cells (DCs) can influence immune responses. The type of DC and the signals it receives from the dying cell determine whether the immune response is immunogenic or tolerogenic. For example, CD8α⁺ DCs are more likely to induce tolerance, while CD8α⁻ DCs promote immunity. The location of dying cells and the cells that engulf them also plays a role in determining the immune response. For instance, intravenous injection of apoptotic cells can induce tolerance in the spleen, while subcutaneous injection can induce immunity. The spleen appears to be an organ of tolerance, while lymph nodes are more involved in immune responses. Receptors on phagocytes that recognize dying cells, such as MFG-E8 and Tim-4, can influence the immune response. The modification of DAMPs during apoptosis can also affect immunogenicity. For example, caspase activation can lead to the release of HMGB1, which can promote immunity, while the absence of caspase activation can reduce immunogenicity. The immune system's response to dying cells is complex and influenced by various factors, including the type of cell death, the signals released, the type of APC, and the location of the dying cells. Understanding these factors is crucial for developing strategies to enhance immune responses against tumors and pathogens while avoiding autoimmune reactions.