Cell death recognition model for the immune system.

It is essential for the immune system to recognize markers or understand rules required for discriminating antigens that should be actively responded to from those be tolerated. Although the classic self-nonself theory over the past five decades has been challenged by "danger" model and "infectious nonself" model, etc., no theories could fit for all. Cell death is important not only for its role in homeostasis, but also for its decisive effects on the immune responses. Different ways of cell death, apoptosis or necrosis, transmit fundamentally opposite driving forces for the immune system, inducing tolerance or initiating adaptive immune responses. The progress in understanding phagocytosis and process of apoptotic and necrotic cells leads the author to propose "cell death" recognition model for the immune system. Four principles are important in this model. First, only antigens shedding from apoptotic or necrotic cells rather than those from healthy cells, can be presented to naïve T cells. Second, either apoptotic cells or necrotic cells, but not healthy cells, can attract phagocytes, namely dendritic cells (DC) or macrophages that are also antigen presenting cells (APC), to scavenge dead cells. Third, macrophages or DC residing in non-lymphoid tissues phagocytose dying/dead cells, migrate to lymphoid tissues and present antigens to naïve T cells there. Fourth, tolerance or adaptive responses are not dependent on whether the antigens are self or nonself, but on the ways of cell death during antigen presentation. Importantly, tolerance and adaptive immunity are all dominant responses and the impact of cell death on immune responses is a dynamic balance between them. "Cell death" recognition model could more easily explain various immune phenomena, including infection, self tolerance and autoimmunity, tumor immunity as well as transplant rejection. Investigation into the roles and mechanisms of cell death mediated immune responses and finding out key modulators will prompt better understanding the ways of immune recognition and provide novel strategies for the management of autoimmunity, tumors, infections as well as transplantation.