Immunogenic and tolerogenic cell death

Abstract

As cells are infected by microorganisms, they can pre-emptively die to prevent the replication and spreading of the pathogen. Cell death that is associated with the presence of pathogen-associated molecular patterns (PAMPs) can stimulate vigorous immune responses. In the absence of PAMPs, damage-associated molecular patterns (DAMPs) produced by dying cells can stimulate an immune response that can elicit the specific recognition of antigens expressed by dying cells (for example, tumour antigens). The nature of the immune response to cell death depends on which cells die, where they die, how they die, which cell engulfs them and when (or if) an associated antigen has been or will be recognized. Variations in these factors can have consequences that range from effective anti-pathogen or antitumour responses to autoimmune pathology. The simple idea that apoptosis is tolerogenic or non-immunogenic and that necrosis is immunogenic is an oversimplification. Thus, apoptosis of tumour cells that is induced by chemotherapy can prime an efficient immune response, which in turn can contribute to the efficacy of antitumour regimens. Various DAMPs contribute to the immunogenicity of apoptotic cell death. These include the surface exposure of chaperone proteins (such as calreticulin) or the release of proteins, such as high-mobility group box 1 protein (HMGB1) and SIN3A-associated protein 130 (SAP130) among others. The catabolic action of caspases and autophagy can also contribute to the immunogenicity of cell death. The tolerogenic effect of cell death depends on many factors, including the absence of T cell help, the location of the dying cells (which in part dictates their engulfment by distinct dendritic cell (DC) subtypes), the maturation state of the DC, the production of immunosuppressive factors (such as transforming growth factor-β) or the modification of DAMPs (for example, oxidation of HMGB1 that results in its inactivation). In conclusion, the mechanisms that determine the immune response to dead and dying cells are complex. Understanding (and possibly manipulating) these mechanisms can have important implications for cancer biology, infectious disease, tissue injury and autoimmunity.