Cell death and the immune system: getting to how and why

This article introduces a series of reviews covering Molecular Mechanisms of Cell Death appearing in Volume 277 of Immunological Reviews. As is the case for all living things, cells die. In most cases, the death of a cell is by an active, regulated process, rather than by simple accumulation of irreparable damage. For several decades, the study of cell death focused predominantly on what is perhaps the best understood of these regulated forms of cell death, apoptosis. In more recent years, however, other forms of active cell death have emerged, and their mechanisms elucidated.1 This volume outlines these diverse modes of cell death, especially as they apply to the immune system. This focus on the immune system, at first glance, would seem inevitable in this series, since they are “Immunological Reviews.” However, when we probe a bit more deeply, several additional (and perhaps more satisfying) rationales for this focus emerge. First, different forms of cell death have distinct effects on the organism, and this is a consequence of how the way in which a cell dies influences the immune response. Secondly, active cell death functions in cases in which “unwanted” cells are culled, and such processes are well represented in the development and homeostasis of the immune system. Thirdly, the process of cell death is, itself, a way in which organisms control intracellular infections, removing the infected cell before the pathogen can replicate (this can be by “suicide” or by “murder,” with similar benefits for the individual). And finally, much of what we have come to understand about the mechanisms of active cell death has come from studies of the immune system, in both healthy and disease states. In this volume, several different modes of cell death are described in the context of the immune system. Originally, the types of cell death were defined by morphological features; however, our understanding of the processes has allowed a more mechanistic characterization that predominates today. Historically, cell death was parsed into three types: apoptosis (type I), autophagic cell death (type II), and necrosis (type 3), but we have learned that these take several forms, depending on the molecular pathways involved.2 These molecular pathways are summarized in Figures 1-4. Apoptosis (Figure 1) is a process wherein the cell is effectively “packaged” for elimination, and this is a function of a subset of the caspase proteases, in particular the executioner caspases, which cleave hundreds of substrates, including those involved in “processing” the cell (chromatin cleavage and condensation, membrane blebbing, and the elaboration of signals for effective clearance).3 There are two major pathways for the activation of the executioner caspases, defined by the roles of other caspases that activate the executioners. One of these, often called the “extrinsic pathway,” is usually engaged by the ligation of death receptors, a subset of the TNF receptor family (but can be engaged by other mechanisms).3, 4 The other, referred to as the “intrinsic, or mitochondrial pathway,” involves the sensing of cellular stress or other signals by proteins of the Bcl-2 family,3, 5 which converge on mitochondria to cause the permeabilization of the mitochondrial outer member, releasing intermembrane space proteins that signal the activation of the caspases. Necrosis is a form of cell death that is distinct from apoptosis, and involves the rupture of the plasma membrane, which can have inflammatory consequences. While necrosis can occur as a passive effect of accumulated damage, we now understand that there are several regulated forms of necrosis in which the cell actively participates in its demise. These include pyroptosis6 (Figure 2), necroptosis7 (Figure 3), and ferroptosis8 (Figure 4), all of which are understood to a great extent at the molecular level. Chapters in this volume describe these processes in some detail. Autophagic cell death, while long described based on morphology, is more problematic. It can result from cell death (either apoptotic or necrotic) that occurs in a cell that is undergoing autophagy; in such cases, the molecules of the autophagy pathway do not participate in dispatching the cell. Bona fide autophagic cell death, in which such molecules do participate, is described largely in invertebrate systems (especially Drosophila) and to a lesser extent in mammalian cell culture.9 It is poorly understood, as is its impact on the biology of the immune system, and is not covered in this volume. In considering these diverse cell death mechanisms, we have greatly advanced our knowledge of how cells die. As the reader will note, however, the evolutionary rationale for distinct forms of cell death, the “why,” emerges only when we consider what dying cells do to the cells around them. And as mentioned above, this is perhaps best understood in the context of the immune response. This volume was planned with this “why” in mind. The first three reviews concern the roles for cell death, primarily apoptosis, in T-cell development and homeostasis. Daley, et al.10 address how apoptosis in the thymus shapes the immune repertoire, functioning in each step of the selection process. Li, et al.11 and Zheng, et al.12 extend these ideas to the periphery, asking how apoptosis influences T-cell numbers in health and disease, and offer insights into how these concepts can be applied to therapy for T-cell-mediated autoimmune diseases. As discussed above, regulated necrosis takes several forms. Perhaps, the most complex of these is pyroptosis, involving the activation of caspase-1 and caspase-11 to promote, not apoptosis, but an important, inflammatory, necrotic process of pyroptosis. Man, et al.13 provide an in-depth investigation of the ways in which pyroptosis is engaged in infection and in non-infectious inflammatory diseases. At the interface of apoptosis (by the extrinsic pathway) and necroptosis are the diverse functions of the receptor-interacting kinases, RIPK1 and RIPK3, and the functions of caspase-8. Tummers and Green14 explore the roles of caspase-8 in promoting apoptosis and inhibiting necroptosis. Extending these concepts to host defense, Upton, et al.15 discuss the roles for apoptosis and necroptosis in viral infection. Orosco and Oberst16 continue with this perspective, asking how RIP kinases function during viral infection to both promote cell death (via apoptosis and necroptosis) and also perform additional functions for antiviral defense. Kondylis, et al.17 further explore the interplay between the cell death mechanisms and the functions of NF-κB, and how this impacts both necroptosis and disease. While necroptosis is thought to have evolved primarily as an antiviral strategy, its potential involvement in cell death-related pathologies has come to light in recent years. Tonnus and Linkermann18 discuss the evidence for regulated necrosis, especially necroptosis, in several pathological conditions that profoundly affect human health. They also introduce the concept of ferroptosis, another distinct form of regulated necrosis and discuss its potential involvement. In the article by Dixon19, the possible roles of ferroptosis in disease are similarly considered, with a perspective on its possible function in normal biological processes. Once a cell dies, by any mechanism, the cells of the innate immune system are engaged in the resulting response, be it inflammatory or anti-inflammatory. The final review by Blander20 explores this critically important process, and how it impacts on disease. This volume marks a critical time in our understanding of the fundamental mechanisms of cell death and their impact on immune function. We have learned a great deal about how cells die, as the reviews herein indicate. But we have also gained an understanding of why cells die by one mechanism or another, and the effects such cell death have on the organism as a whole. These insights have profound implications for future therapies for the treatment, not only of cancer (where most efforts have been directed) but also of autoimmunity, inflammatory disease, and other pathologies, as these reviews attest. As we gain understanding of how to manipulate specific cell death pathways, we will see how the application of our knowledge to human disease not only impacts the health of patients, but also where our ignorance lies. D.R.G. is supported by grants from the US National Institutes of Health, the Lupus Research Alliance, and ALSAC. The author declares no conflicts of interest.