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Caspases, Bcl-2 Family Proteins and Other Components of the Death Machinery: Their Role in the Regulation of the Immune Response

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The prime directive of the immune system is to defend the host. The threats can be external in the form of microbial pathogens or internal in the form of rebellious autoreactive or malignant clones. The central dogma is that infected or aberrant cells must be destroyed quickly and innocuously to avoid significant cellular conflict and pathology. Apoptosis is the molecular program used by the immune system to implement the prime directive. The program is used to activate a set of caspases, which destroys cells that have been targeted to die. The apoptotic program can be activated internally when the molecular operating system detects cellular perturbations or externally via death ligands. It is critical for the development, maintenance and effectiveness of the immune system. As with any program it is susceptible to corruption and internal errors, which can result in host pathology.

Introduction

Programmed cell death is fundamental to the development, function and maintenance of the immune system. The apoptotic program is critical for the day-to-day running of both the innate and acquired arms of the immune system.1 It is important in host defence against pathogens and perhaps cancer. However, when things go wrong and the program crashes or is hijacked and corrupted by pathogens the normal physiological immune response is replaced by pathological processes. For example, excessive cell death has been observed in some infections and inappropriate lymphocyte survival can lead to autoimmune disease or malignancies of the hemopoietic system.2–4

The apoptotic program utilizes as part of its hardware a set of aspartate-specific cysteine proteases called caspases, which systematically dismantle the cell.5 These enzymes that cleave and consequently destroy critical cellular substrates are normally maintained in an inactive zymogen state so that the default switch setting is off.6 It is only when one of the elaborate cellular subroutines and sensors is activated that the master downstream program is triggered and the switch is thrown to activate effectors of apoptosis.

In this chapter we will explore the role of apoptosis in both the normal physiological functioning of the immune system and also in pathological disease states. We will dissect the elaborate subroutines that control the apoptotic program. We will meet such players as FADD (also called MORT1) that function as adapters to coordinate the flow of extracellular data to the central processing unit, which initiates the effector program subroutine.

Overview of the Immune System

The Purpose of an Apoptotic Program

The primary function of the immune system is host defence and surveillance. It must recognize and eradicate pathogens and aberrant cells but must leave normal cells unharmed. Consequently the immune system must incorporate a program that facilitates the killing of pathogens and also a fail-safe suicide program for removal of self-reactive clones that would otherwise attack normal tissues.7,8 Self-tolerance and removal of autoreactive lymphocytes is essential for normal immune function.

The immune system has two arms, an innate defence system and an acquired response element. The innate immune response consists of the ready and immediate host defences including physical, chemical and microbiological barriers.9 The cellular elements of the innate system are phagocytic cells including neutrophils, monocytes and macrophages,10 cells that release inflammatory mediators including basophils, mast cells and eosinophils11 and executioner cells called natural killer cells.12 The phagocytic cells have an arsenal of weapons including cytokines such as interferon and free radicals. The other molecular components of the innate response include complement and acute phase proteins. These mechanisms are highly conserved through evolution and function as the first and only line of defence in many species that have no adaptive immune system.13

The acquired or adaptive immune response requires priming with antigen and the effectors are T and B lymphocytes. The two arms are highly integrated.14 Early defence is coordinated through the innate arm. It is non-specific but rapid, whereas the adaptive response takes some time to coordinate but is specific to the invading pathogen.15 Moreover, the adaptive arm develops memory and on rechallenge with the same pathogen it arms quickly and is able to deploy rapidly and decisively.16 Apoptotic cell death plays a role in both arms of the immune system. It is involved in destruction of infected cells and in down-regulating the adaptive immune response.1

The Innate Immune Response and Apoptosis

The apoptotic program and caspases are inherent to all cells. Cellular perturbations caused by virus infection can trigger a trip wire that activates the cell suicide program. In the majority of cases this aids in the elimination of virus at the expense of the host cell and constitutes an early and ready defence in the innate immune system.1,17 The importance of this apoptotic program in innate immunity is highlighted by the number of anti-apoptotic mechanisms that viruses have developed to either avoid triggering the program or inactivate the operating system.1 Activation of the apoptotic program in an aberrant form is sometimes deleterious to the host. Viruses may commandeer the program and use it to their advantage in destroying host tissue, thereby facilitating viral dissemination.

The Adaptive Immune Response and Apoptosis

When the adaptive immune response is primed with antigen, one of the major mechanisms by which T lymphocytes kill infected cells (those that have not already committed suicide) is by activating the apoptotic program and associated caspases in these cells. This is achieved by two mechanisms, either by signalling through death receptors (like Fas/APO-1/CD95 and TNF-R1) or through the action of perforin and granzymes.18 When the pathogens have been cleared and the adaptive response changes to standby mode, many of the expanded T lymphocyte effector cells are deleted by apoptosis probably to prevent inappropriate tissue destruction or lymphadenopathy, which can be a forerunner of malignancy.19

Overview of the Apoptotic Program, the Operating System and Caspases

Activation of the cellular suicide program results in a characteristic type of cell death called apoptosis.20 This program is intrinsic to all cells that make up vertebrate and invertebrate multicellular animals including nematodes, insects and mammals.21,22 The program has been conserved during the evolution of the animal kingdom and the final executioners are invariably caspases. Caspases can be divided into two groups according to their structure and function: “initiator caspases” and “effector caspases”.5 The former have characteristic protein-protein interaction domains that facilitate binding to adaptor proteins. Caspase-8 and caspase-10 (the latter is present in humans but not mice) have two death effector domains (DED) through which they interact with the adaptor protein FADD that has a single DED motif.23,24 Caspase-1,- 2, -4, -5, -9, -11 and -12 have a different interaction domain called caspase recruitment domain (CARD).5 Caspase-9 through its CARD domain and by way of a homotypic interaction is able to bind the adaptor Apaf-1 which also has a CARD motif.25–27 Adaptor molecules function to aggregate the initiator caspase zymogens and the induced proximity allows their low-level enzymatic activity to effect autocatalytic processing and throw the death switch on.28 The autoactivated initiator caspases are then able to process and activate effector caspases including caspases-3, -6 and -7.5 This sets in train a series of cascading and amplifying activation subroutines that proceed inexorably to cell collapse as critical cellular proteins are proteolytically destroyed. Caspase after caspase becomes activated and in turn inactive enzymes like CAD (caspase activated DNase) are liberated from their shackled state to become active and destructive proteins that, in the case of CAD, chew up the instruction code library of life, DNA.6 Various sensors in the cell that detect intracellular perturbations or external death signals initiate the apoptotic program.29,30 Mammals have two distinct pathways that converge and feed into the central apoptotic processing unit with its effector caspases.31 The two pathways utilize different adaptor molecules and different initiator caspases.

The Death Receptor Pathway to Cell Death

Cell death can be induced through certain cell surface receptors that belong to the tumor necrosis factor receptor family (TNF-R).32 These “death receptors” share, in their cytoplasmic portion, a homologous sequence called the death domain.32–36 Interactions between such death receptors and their ligands are important in several physiological processes. The downregulation of specific adaptive immune responses is in part achieved by inducing apoptosis in activated T cells via death receptor ligation.19 Moreover expression of death ligands provides T cells and other cells of the immune system with a means to externally activate the apoptotic program in infected or aberrant cells that must be detected during immune surveillance.32 When death ligands bind to their cognate death receptors they cause clustering of the receptors and their death domains. This clustering recruits, via a homotypic interaction, adaptor proteins that also have a death domain such as FADD and TRADD (Fig. 1).35–37 The death ligand, FasL, binds and oligomorizes its receptor Fas (CD95/APO-1) and clustering of Fas then facilitates the recruitment of the adaptor protein FADD. In the case of TNF-R1 and, perhaps certain other death receptors, the intermediary adaptor TRADD is required before FADD can be recruited to activated receptors.32 When FADD binds to Fas or other death receptors it is able to recruit procaspase-8 (and in humans also procaspase-10) via the DEDDED interaction described above.23,24 Procaspase-8 (and procaspase-10) have low inherent activity but when they are recruited and clustered by FADD a critical level is achieved and the recruited zymogens are able to activate each other.38,39 The activated caspase-8/-10 molecules then set off the apoptotic chain reaction. Caspase-9 and its adaptor Apaf-1 are not required in the cell death program initiated through the clustering of cell surface death receptors.38–44 These elements form part of a different operating system that ultimately converges with the death receptor induced apoptotic pathway at the point of effector caspase activation.

Figure 1. Apoptosis can be induced via death receptor signalling.

Figure 1

Apoptosis can be induced via death receptor signalling. FasL, TNF and TRAIL bind to their cognate receptors and recruit adaptor proteins FADD and TRADD. Caspase-8 is aggregated and activated to complete the death inducing signalling complex (DISC). Downstream (more...)

The cell surface death receptors have functions other than activating the apoptotic program. Ligation of TNF-R1 and some related receptors can activate transcription factors NF-κB and AP-1 via recruitment of various adaptor proteins and kinases like TRADD, RIP, NIK and TRAFs. Active NF-κB is in turn able to upregulate the expression of genes involved in inflammatory responses.32,45 TNF upon binding to TNF-R1 can switch on the death program and instruct the cell to commit suicide or, if the death program is disabled for one or other reason, it can instruct the cell to survive and produce inflammatory cytokines.46–48 The latter instruction set is issued more commonly probably because NF-κB is able to switch on genes that disable or deactivate the apoptotic program. The dual nature of death receptor signalling is an integral component of the “fuzzy logic” that the system uses to decide whether a cell should die or survive. The cell may receive many internal and external signals that contribute to a cellular milieu that is either conducive or obstructive in activating the apoptotic program.

FLIP molecules constitute one of the negative regulators of death receptor induced apoptosis. They resemble caspase-8 but do not possess its enzymatic activity. FLIP can bind to activated FADD and thereby prevent the processing of caspase-8 and inhibit or interfere with the death receptor program.49 Surprisingly in addition to its role in apoptosis, FADD may be critical in signalling pathways that promote cell proliferation and growth.50–52 Like TRADD, which is able to flick the switch between activation of the cell death program and activation of the pro-survival and inflammatory pathway, FADD may have two faces and a dual role.

The Intrinsic Pathway to Cell Death

The operating system underpinning the intrinsic pathway involves regulatory elements known as the Bcl-2 family members. These members can be loosely divided into two groups, those that negatively regulate and those that positively regulate the intrinsic cell death program. Although caspase-8 and the adaptor FADD are essential elements of the apoptotic program induced by death receptor ligation, they are not involved in the apoptotic program activated by growth factor deprivation, glucocorticoids or DNA damage.31,51,53–56 The initiator caspase-9 and the adaptor protein Apaf-1 are involved in the intrinsic apoptotic signalling program. Their role however, is not indispensable because at least in certain cell types overexpression of Bcl-2 or loss of certain pro-apoptotic Bcl-2 family members causes more severe apoptotic defects than loss of Apaf-1 or caspase-9.

The mammalian Bcl-2 protein family comprises at least 24 members encoded by 20 genes.57 The various members function as sensors of cellular stress and they receive input from various sources including the endoplasmic reticulum, the cytoskeleton, the nucleus and the mitochondria (Fig. 2). The archetypal family member called Bcl-2 and its pro-survival homologues process most of the information collected by these sensors. Bcl-2 was the first member to be discovered when the encoding gene was found to be translocated in human follicular lymphoma.58 Bcl-2 protects cells from growth factor deprivation or against exposure to cytotoxic drugs, taxol, cisplatin, glucocorticoids or ionising radiation.59–62 However, it is not able to effectively abrogate the death program when it is activated by death receptors, at least in lymphocytes and myeloid cells.31,63–67

Figure 2. The pathways to death.

Figure 2

The pathways to death. Apoptosis can be induced by death receptor signalling and DISC formation or via the activation of the intrinsic apoptotic program. The Bcl-2 family members form the backbone of the intrinsic apoptotic pathway. Growth factor deprivation, (more...)

Seven of the Bcl-2 family members, Bcl-2, Bcl-XL,68 Bcl-w,69 Boo,70 A1,71 Mcl-172 and Bcl-B73 can inhibit apoptosis.57 All the anti-apoptotic members share 3 or 4 homology domains called BH (Bcl-2 Homology) regions and they localize to the outer mitochondrial membrane and the cytoplasmic faces of the endoplasmic reticulum and nuclear envelope.74–76 Seventeen other Bcl-2 family members promote apoptosis. These members include Bax,77 Bcl-xs (a splice variant of the bcl-x gene),68 Bak,78–81 Bok/Mtd,82,83 Bad,84 Bik,85 Bid/Nbk,86 Hrk/DP5,87,88 Blk,89 Bim/Bod,90 Noxa,91 Puma/Bbc3,92–94 Bcl-GL (long), Bcl-Gs (short)95 and Bmf.96 These pro-apoptotic members can be divided into two subgroups depending on the number of Bcl-2 homology domains they possess. Bax, Bok, Bak, Bcl-GL and Bcl-Xs have multiple BH domains whereas Bik, Blk, Hrk, Bim, Bad Bid, Bcl-Gs, Puma, Noxa and Bmf only possess the short (9 to 16 residue) BH3 region and hence are sometimes called BH3-only proteins.97

The pro-apoptotic and anti-apoptotic Bcl-2 family members can physically interact and in some cases antagonize each other.77,98 This is particularly important in the case of the BH3-only pro-apoptotic members because their ability to induce apoptosis is dependent on their ability to bind and antagonize the pro-survival members.78,90,96,99 Many of the BH3-only proteins are sequestered from the pro-survival members in healthy cells so that antagonistic interactions are minimized. However, when these BH3-only stress sensors are activated they are liberated and they can block the pro-survival members and thereby activate the apoptotic program. For example, Bim and Bmf are sequestered to the microtubular dynein motor complex100 and the myosin V actin motor complex respectively.96 Certain apoptotic stimuli can cause release of Bim or Bmf and allow them to translocate to and antagonize the pro-survival Bcl-2 proteins, thereby initiating the apoptotic caspase cascade.

It is not clear how the multidomain pro-survival Bcl-2 family members are able to maintain the apoptotic program in a repressed state but somehow they must interfere with the activation of initiator caspases. In the case of caspase-9, the adaptor protein Apaf-1 is required to cluster the proenzyme and facilitate its autocatalytic activation. Apaf-1 mediated clustering of caspase-9 into an apoptosome requires the presence of cytochrome c, which is normally located inside the mitochondria.26 Bcl-2 could either directly or indirectly regulate the activity of Apaf-1 or other adapters or it could prevent the release of cytochrome c from the mitochondria.101–105 We believe that the Bcl-2 family members inhibit the activity of Ced-4/Apaf-1 related molecules and that the mitochondrial release of cytochrome c may function as an amplifier or positive feedback loop in the apoptotic cascade.106 The pro-apoptotic molecules Bax and Bak are required to effect death induced by the BH3-only proteins and, Bcl-2 and its homologues appear to maintain Bax/Bak related proteins in an inactive state.107,108 The BH3-only proteins may directly or indirectly, by inactivating Bcl-2, promote the activation of Bax and Bak and thereby initiate the caspase cascade.

The ratio between pro-survival and pro-apoptotic Bcl-2 family members determines which direction the switch is flicked, cell death or cell survival. The levels and activity of pro and anti-apoptotic Bcl-2 family members can be regulated by cytokines. Certain cytokines, such as IL-7, can upregulate the production of pro-survival Bcl-2 family members.109–112 The amount or activity of pro-apoptotic Bcl-2 family members can also be regulated by extracellular ligands.96,100,113,114

DNA damage or cell cycle aberrations can induce cell death via a program subroutine that involves the tumor suppressor p53.62,115,117 The mechanism by which p53 is able to activate the apoptotic program is unclear but it may involve increasing the expression of the pro-apoptotic (BH3-only) Bcl-2 family members Noxa or Puma.91,94 The p53 apoptotic program ultimately utilizes the standard intrinsic operating system with caspase-9 and Apaf-1 to facilitate effector caspase activation40–43,118 and it can be antagonized by pro-survival Bcl-2 family members.62

The Caspase Hardware

Regardless of the initiating event or the path taken, the final subroutine of the apoptotic program is common to all and involves the activation of effector caspases that function as the executioners of the cell death. Apart from their involvement in the apoptotic program, caspases can also be involved in other cellular processes. Caspases-1 and -11 have proinflammatory roles, as they are required for the processing of IL-1β and IL-18.119–123 Indirectly they also control the production of IL-1α, IL-6, tumor necrosis factor-α (TNF) and interferon-γ (IFN-γ) in response to lipopolysaccharide (LPS) stimulus. Indeed mice that are deficient in caspase-1 do not succumb to a septic shock syndrome normally induced by LPS injection.122–124 Caspase-1 and caspase-11 deficient mice have no obvious abnormalities in developmental cell death.123,124 Therefore it is believed that these caspases play no role in programmed cell death. Alternatively, they could have an important but redundant role that would only manifest in mice lacking two or more initiator caspases.

Mice deficient in caspase-8 die during embryogenesis due to defective myocardial development and they have reduced numbers of hemopoietic precursor cells.56 This may indicate that caspase-8 has a role in cell growth and proliferation in addition to its role in death receptor induced apoptosis. Alternatively the phenotype may be due to defective apoptosis in other cells required for normal myogenesis. Mice lacking the initiator caspase-9 have brain overgrowth due to reduced apoptosis in neuronal tissue.40,41 Caspase-3 deficient mice show a similar but slightly less profound defect in the central nervous system.125 The effects of caspase-9 and caspase-3 deficiencies in lymphoid and myeloid cells are not very severe indicating that other initiator and effector caspases may be more important for apoptosis in the hemopoietic system. Mice lacking caspase-2 have only minor abnormalities126 and mice lacking caspase-12 develop normally, but their cells are relatively resistant to ER stress induced apoptosis.127

Granzyme B, a serine protease, can induce apoptosis by processing caspases at the P1 position.128 Granzyme B released by T cells realizes its homicidal potential by activating caspases in target cells and thus activating the final elements of the apoptotic program.129–131

Deciphering the Operating Language of the Apoptotic Program in the Immune System

Most of our understanding of the apoptotic operating language comes from transgenic or gene knockout studies in mice.

Dissecting the Death Receptor Pathway

A deficiency of caspase-8 is embryonic lethal in mice possibly due to a cardiac defect. Embryonic fibroblasts obtained from caspase-8-deficient mice are completely resistant to death receptor induced apoptosis.56 Caspase-8, therefore, is an essential element of the death receptor pathway despite reports that caspase-2 might be able to substitute for it in receptor-associated apoptosis.126 Studies using transgenic mice that express CrmA, an inhibitor of caspase-8, in lymphocytes show that these lymphocytes are resistant to death receptor-induced apoptosis.54 Mice that have defects in FasL or Fas show a similar resistance to death receptor-induced apoptosis, but in addition these mice develop T-cell hyperplasia and high levels of autoantibodies.33 Mice deficient in FADD die during embryogenesis with a phenotype similar to that of caspase-8-deficient mice.50,53 Interestingly, mature T cells that express a dominant interfering mutant of FADD (FADD-DN) or lack FADD show a reduced proliferative potential in response to mitogens or antigens.50,52 In contrast, lymphocytes from transgenic animals expressing CrmA proliferate normally in response to mitogenic stimulation, as do lymphocytes from mice with defective FasL or Fas.51,54 Although the phenotype of the caspase-8-deficient mouse lends support to the theory that caspase-8 may be involved in the control of cell proliferation, the CrmA transgenic studies indicate that caspase-8 does not have a critical role in cell proliferation.

Thymocyte development and selection is dysregulated when the function of FADD is blocked. At an early stage of development CD348 pro-T cells differentiate to become CD4+8+ thymocytes after assembly of a functional T cell receptor β chain. Those cells that are unable to assemble a functional TCR β chain are culled at the pre-TCR checkpoint, but this is not the case in thymocytes expressing FADD-DN or in FADD-deficient pro-T cells from chimeric mice.132,133 Interestingly, this phenomenon is not seen in mice lacking Fas, which indicates that other (death) receptors must be involved in this culling process. The normal proliferation of thymocytes as they progress from the CD348pro-T to the CD3+4+8+ thymocyte stage is severely impaired by FADD-DN expression.133 Thus, FADD plays a critical role in cell death and cell proliferation at the pre-TCR checkpoint.

It has been suggested that there is an element of cross talk between death receptor-induced apoptotic signalling and the intrinsic apoptotic program. Evidence suggests that activated caspase-8 can cleave Bid (a pro-apoptotic BH3-only Bcl-2 family member) to a truncated form, which is then able to activate the intrinsic pathway and thus amplify the apoptotic program.105,134,135 Bid-deficient mice show some resistance to Fas-induced hepatocyte apoptosis but their lymphocytes are normal and remain sensitive to Fas-induced killing.136 Thus, Bid may play a role in amplifying the death receptor signal through the intrinsic Bcl-2 apoptotic pathway in some but not all cells. Indeed, since Bid can also be cleaved by caspases other than caspase-8,105,134,136 it may play a more general role as an amplifier in apoptosis signalling.

Dissecting the Intrinsic Apoptotic Signalling Pathway

Mice deficient in Bcl-2 have a defect in keeping mature lymphocytes and myeloid cells alive.137 Differentiated T and B cells are highly vulnerable to accidental activation of the intrinsic apoptotic pathway. Bcl-2-deficient mice are born runted and within a few months die from renal failure secondary to polycystic kidney disease and they have excessive melanocyte death and neuronal cell death postnatally.137,138

Bcl-X has two isoforms, Bcl-XL and Bcl-Xs, which inhibit or promote apoptosis, respectively.68 Mice that lack both isoforms die during embryogenesis due to overwhelming apoptosis of postmitotic differentiating neurons and fetal liver hemopoietic cells.139 In an attempt to understand the relevance of Bcl-X in the immune system chimeric mice have been generated. In these mice mature Bcl-X-deficient T and B cells function normally but immature CD4+8+ thymocytes are abnormally prone to apoptotic cell death.139,140 This is in contrast to the Bcl-2-deficient animals described above in which lymphopoiesis proceeds normally but mature lymphocyte survival is severely impaired. This correlates precisely with the levels of each of these molecules in the respective cell types. A1-deficient mice have accelerated apoptosis in their neutrophil populations141 and embryos lacking Mcl-1 die prior to implantation.142 Transgenic overexpression of Bcl-XL or Bcl-2 makes thymocytes resistant to a variety of apoptotic stimuli including gamma irradiation, glucocorticoids, and anti-CD3 treatment.60–62,144 Overexpression of Bcl-XL within B lymphocytes causes marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells in transgenic mice.145

Transgenic overexpression of Mcl-1 in hemopoietic cells enhances their viability when cells are cultured in vitro, particularly in cells of the myeloid lineage, but homeostasis is maintained with normal cell numbers in the whole animal.143

Mice lacking the BH3-only pro-apoptotic Bcl-2 family member Bim show aberrations in thymic development and their mature T and B cells do not die upon cytokine withdrawal. Consequently, these mice develop lymphadenopathy, splenomegaly and elevated levels of immunoglobulin with plasmacytosis.146 Over 50% of Bim-deficient mice die during embryogenesis of unknown causes and many of those born die by one year due to SLE-like autoimmune complications with immune complex deposition in renal glomeruli and a vasculitis.146

The immune system, in an attempt to produce a large and varied repertoire of T cells that can recognize the spectrum of foreign antigens, produces as a by-product T cells that recognize and could potentially be harmful to self. Autoreactive T cells must be deleted in the thymus or in peripheral lymphoid organs to protect the host from rebellious and self-destructive clones.147 Apoptosis is responsible for the culling of autoreactive T-cells in the thymus.148–150 This process is termed thymic negative selection. Cells that somehow escape this process may still be deleted in the periphery.151 Given the thymic and peripheral T cell aberrations seen in Bim-deficient mice, Bim could be one of the pro-apoptotic molecules involved in negative selection.146,239

Bax deficient animals have very mild hemopoietic abnormalities and they also show a degree of neuronal hyperplasia.152,153 Bak deficient mice appear normal.154 Crosses between Bax- and Bak-deficient animals generate Bax−/−Bak−/− mice with lymphocytes and fibroblasts (and perhaps other cell types) that are refractory to many death stimuli that activate BH3-only proteins.107,108,154 These mice showed persistence of interdigital webbing and develop progressive lymphadenopathy.154

When the Program Crashes or Is Corrupted

Cancer

Apoptosis is involved in the removal of aberrant cells that might otherwise give rise to tumors.4 Mutations leading to reduced activity of pro-apoptotic Bcl-2 members, or mutations causing overexpression of pro-survival genes, promote tumorigenesis. Bax is mutated in some leukeamias155 and translocation of the bcl-2 gene with its subsequent overexpression has been demonstrated in most follicular lymphomas and in some cases of chronic lymphocytic leukemia and diffuse large cell lymphoma.57 Bcl-2 transgenic mice develop lymphoid hyperplasia that can in turn develop into lymphomas.156–160

Many B lymphoid tumors have a translocation of the myc gene, which enhances cell proliferation and thereby contributes to oncogenesis. Deregulated Myc expression promotes cell cycling but also lowers the threshold for activation of the apoptotic program.161–163 Mice that overexpress Myc and have the apoptotic program deactivated by overexpression of Bcl-2 develop lymphomas and mammary carcinomas at a rate that exceeds that seen in mice overexpressing either of the two oncogenes alone.157,164,165

Resistance to Fas-induced apoptosis has also been implicated in tumorigensis.166–169 Human B non-Hodgkin's lymphoma cells are resistant to killing caused by agonist anti-Fas-antibodies.170,171 Aberrations in Fas signalling could make malignant cells partially resistant to cytotoxic T cell mediated killing, but they remain sensitive to the action of perforin and granzymes.172,173 It is not clear whether this or other consequences of deranged Fas signalling are responsible for transformation. Rag-1-deficient mice, in which the function of FADD has been blocked by transgenic expression of FADD-DN, develop thymic lymphomas over time.133 FLIPs may be involved in deactivation of the death receptor program but evidence implicating their involvement in lymphoma disease is only circumstantial to date.174,175

Implications for Cancer Treatment

Chemotherapy used in the treatment of lymphoid malignancy can induce apoptosis of the rogue cells.176 If the apoptotic program is impaired, cells could potentially become resistance to chemotherapy. It has been suggested that inactivation of p53 and/or overexpression of Bcl-2 (or any of its pro-survival homologues) is associated with chemotherapy and radiotherapy resistance.62,177 Indeed, the tumor suppressor gene p53 is mutated in many types of cancer.178 It is still controversial as to how important deactivation of the apoptotic program is in determining chemotherapy and or radiotherapy resistance in tumors that are not of hemopoietic origin.179

Autoimmunity

Cells of the immune system have an enormous potential to expand in response to stimulation. This is critical for their ability to deal with and eliminate invading organisms. The corollary of this, however, is that lymphocytes can develop into a dangerous population of cells if their growth and activity is not kept in check. We have speculated, on the basis of knockout studies, that the pro-apoptotic BH3-only protein Bim could play a role in negative selection in mice. Bcl-2 overexpression can interfere with the process of thymic negative selection,60,61,180 but death receptor signaling via FADD and caspase-8 does not contribute to this process.51,54

Autoreactive T cells that escape thymic negative selection can still be deleted in the periphery to avoid the development of autoimmune disease. There are two potential ways in which such escapees can be dealt with in the periphery. One mechanism involves activation of death receptors and the other is triggered by limiting availability of essential growth factors.151 T cells upregulate expression of death receptors in response to antigen stimulation and this primes their extrinsic apoptotic program.19,181,183 Autoreactive clones that repeatedly make contact with self-antigen in the periphery will be particularly susceptible to death ligand-induced apoptosis. Indeed lpr and gld mutant mice that have impaired death ligand-mediated apoptosis, because of mutations in the Fas or Fas ligand gene, develop lymphoproliferative disorders and autoimmune disease.184 If wild-type Fas is restored in T cells of lpr mice they do not develop lymphoproliferative disease but they still succumb to autoimmune disease.185 Therefore, Fas induced death or signaling in T cells alone is not sufficient to prevent autoimmune disease.

In humans defective Fas signaling is the likely cause of a particular syndrome comprising lymphadenopathy and an SLE-like autoimmune disease called ALPS.186,187 In type 1 ALPS there is a defect in Fas or FasL, but in a proportion of patients (ALPS type II) these defects are not present yet the patients still display an ALPS phenotype.188 Capase-10 mutations have been defined in these cases,189 but others suggest that these may just represent coincidental non-pathological polymorphisms of the gene locus given that a large proportion of healthy people carry these changes.190

Deletion of activated T and B cells can also be achieved by starving them of cytokines (in particular IL-2 in the case of T cells and IL-6 in the case of plasma cells). Withdrawal of these factors induces apoptosis via activation of the intrinsic program and this can be blocked by Bcl-2.60,61,109,111,191 Bim-deficient lymphocytes are resistant to apoptosis induced by cytokine deprivation.146 Moreover, B cells from transgenic mice that overexpress Bcl-2 are resistant to intrinsic death stimuli and the mice show sustained humoral immune responses with a plasmacytosis and consequently high level of serum immunoglobulins.191 Bcl-2 overexpression or loss of Bim, on certain genetic backgrounds, leads to a fatal SLE-like autoimmune disease with high levels of autoantibodies to nuclear antigens.146,191

TNF-R Family Members Making Life and Death Decisions

We have met some of the TNF-R family members already in the form of death receptors like Fas, TNF-R1 and TRAIL receptors (DR4 and DR5). There are, however, other TNF-R family members, such as TNF-R2, CD30 and CD40, which do not signal death because they do not contain a death domain.192 These receptors can still potentially trigger apoptosis indirectly by inducing the expression of membrane-bound TNF, which then causes cell death through paracrine or autocrine TNF-R1 activation.193 Recently, the BAFF receptors TACI, BCMA, and BAFF-R have been discovered. These receptors are distant relatives of the TNF-R family.194–201 Signaling through these receptors inhibits the intrinsic apoptotic program in B cells, which is normally activated by B cell receptor ligation. Signaling through the BAFF receptors and also CD40 leads to increased levels of Bcl-2 in B cells, possibly by activating the NF-κB pathway, and this inhibits the intrinsic apoptotic program.202–204 Increased levels of BAFF are found in certain strains of mice that develop SLE and transgenic mice that overexpress BAFF develop B-cell lymphadenopathy, plasmacytosis and an SLE-like autoimmune disorder.194,203,205,206 Activated B cells like T cells tend to commit suicide unless they are protected by the presence of growth factors. In the case of B cells these factors are likely to be CD40L and BAFF.

Infectious Diseases

The apoptotic machinery is integral to the function of the innate immune system.207 Viruses encode a vast artillery of proteins that deactivate or corrupt the apoptotic program at practically every point including Fas death receptors, Bcl-2 members and caspases.1 These proteins deactivate the apoptotic program to permit viral latency or corrupt and activate the program to facilitate viral dissemination.208

The first tripwire encountered by viruses attempting to infect cells is at the point of cell attachment. HIV has a viral coat protein called gp120 that attaches to the lymphocyte surface receptor CD4 and the chemokine receptors CCR5 or CXCR4.209 Soluble or membrane-associated gp120, on the surface of infected cells, can induce apoptosis in uninfected cells and this may contribute to viral pathogenicity.210

The Toll receptor family is a set of cell surface receptors used by the innate immune system to sense and signal the presence of microbes.211 All bacteria express bacterial lipoproteins and these are potent activators of the Toll signaling system via Toll receptors (TLR).212,213 Engagement of TLRs initiates a cascade of cellular signals that results in the activation of NF-κB, which regulates the expression of genes involved in inflammation and cytokine production. In addition, like the TNF-R family, TLRs via the adaptor protein MyD88 can recruit FADD, activate caspase-8 and thereby initiate apoptosis.214 In essence then, the innate immune response through the Toll receptors can mobilize the immune forces and also instruct certain cells to die.

Cytotoxic T lymphocytes constitute a major arm of the adaptive immune system. One of their primary roles is to defend the host in the event of viral infection. CTLs kill virally infected cells by releasing perforin and granzymes and by expressing FasL, TNF and perhaps other ligands that activate the death receptor program in target cells.215–217 Viruses have evolved mechanisms to inhibit this form of killing by downregulating cellular expression of MHC class I proteins so that the infected cells are no longer recognized by the immune system. This is highly effective, for as long as infected cells remain incognito they will not be detected by T cells and hence they will not be targets for death ligand or perforin/granzyme induced apoptosis. Certain viruses have evolved strategies to downregulate the expression of death receptors to directly prevent this form of killing.218–220 Other viruses code for proteins that inhibit death receptor induced apoptosis by interfering with FADD/MORT1-mediated activation of caspase-8. Cytomegalovirus encodes a protein called vICA that binds to and inactivates caspase-8.221 Many γ-herpes viruses encode a protein homologue of FLIP, called vFLIP, and adenovirus encodes the inhibitor RID/E3-14.7K.222–225

Given that pro-apoptotic Bcl-2 family members function as sensors of cellular perturbations, they may induce apoptosis if viral infection is detected. Therefore viruses have developed a whole array of Bcl-2 related death suppressors to prevent apoptosis.17,226,227 Epstein-Barr virus (EBV), Human Herpes Virus 8 (HHV8) and adenovirus produce BHRF-1, KSbcl-2 and E1B-19K, respectively.228–231 HIV encodes the protein “tat” that increases the transcription of cellular Bcl-2.232

Depending on circumstances, pathogens may attempt to inhibit apoptosis to allow replication or alternatively they may promote apoptosis to facilitate dissemination and transmission and in doing so cause disease. Many of the pathogenic effects of viruses are due to excessive apoptosis. This is particularly the case with neurotropic viruses that induce apoptosis to produce disease233 and with HIV, which enhances lymphocyte apoptosis induced by death receptors.234,235 The bacteria Neisseria meningitides and gonorrhoreae produce porins that either stabilize or destabilize the mitochondrial membrane potential, respectively. This can prevent or accelerate cytochrome c release and is thought to downregulate or enhance the apoptotic amplification loop, respectively.236,237 Cytomegalovirus may target the mitochondria by a different mechanism using the viral protein vMIA that may inhibit apoptosis.238

Viruses usually attempt to commandeer the host cell replication and cell cycle machinery. Cell cycle perturbations activate p53 and thereby activate the intrinsic apoptotic program. Many viruses, therefore, encode proteins that antagonize the action of p53. These include adenovirus E1B-55K, human papillomavirus E6 and Simian virus 40 T-antigen proteins.1

Concluding Remarks

The apoptotic program with its two operating systems, one activated by death receptors and the other regulated by Bcl-2 family members, does not function in isolation. The program is necessarily subject to regulation from external and internal influences which dictate when, how, why, where and which cells die. Apoptosis and caspases are integral to the immune system. This system must develop, be instructed, cycle between massive expansion and catastrophic death, rebellious clones must be defeated, infectious agents must be eliminated and the prime imperative is to protect the host at any expense. The program itself is vulnerable to crashes, fatal errors and corruption that can result in disease. A better understanding of the operating system, the software and hardware will assist us in attempts to repair or manipulate the apoptotic program to prevent or treat diseases.

Acknowledgments

We thank Vanessa Marsden for assisting in the preparation of figures. Work in our laboratory is supported by grants and fellowships from the Leukemia and Lymphoma Society of America, the NHMRC (Canberra), the Dr. Josef Steiner Cancer Research Foundation (Bern), and the Anti Cancer Council of Victoria (Melbourne).

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