The complex interplay between autophagy, apoptosis, and necrotic signals promotes T-cell homeostasis

Intense research efforts over the last two decades have focused on establishing the significance of apoptotic signaling in adaptive immunity. Without doubt, caspase-dependent apoptosis plays vital roles in many immune processes, including lymphocyte development, positive and negative selection, homeostasis, and self-tolerance. Cell biologists have developed new insights into cell death, establishing that other modes of cell death exist, such as programmed necrosis and type II/autophagic cell death. Additionally, immunologists have identified a number of immunological processes that are highly dependent upon cellular autophagy, including antigen presentation, lymphocyte development and function, pathogen recognition and destruction, and inflammatory regulation. In this review, we provide detailed mechanistic descriptions of cellular autophagy and programmed necrosis induced in response to death receptor ligation, including methods to identify them, and compare and contrast these processes with apoptosis. The crosstalk between these three processes is emphasized as newly formulated evidence suggests that this interplay is vital for efficient T-cell clonal expansion. This new evidence indicates that in addition to apoptosis, autophagy and programmed necrosis play significant roles in the termination of T-cell-dependent immune responses.