Immunogenicity Host Defense, Inflammation, and True Grit

True Grit: Programmed Necrosis in Antiviral Host Defense, Inflammation, and Immunogenicity

This information is current as Edward S. Mocarski, William J. Kaiser, Devon of September 23, 2021. Livingston-Rosanoff, Jason W. Upton and Lisa P. Daley-Bauer J Immunol 2014; 192:2019-2026; ; doi: 10.4049/jimmunol.1302426

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Brief Reviews Immunology

True Grit: Programmed Necrosis in Antiviral Host Defense, Inflammation, and Immunogenicity Edward S. Mocarski,*,† William J. Kaiser,*,† Devon Livingston-Rosanoff,*,† Jason W. Upton,‡ and Lisa P. Daley-Bauer*,† Programmed necrosis mediated by receptor interacting bris to promote Ag cross-presentation by dendritic cells (DCs), protein kinase (RIP)3 (also called RIPK3) has emerged thereby supporting a robust adaptive immune response that as an alternate death pathway triggered by TNF family ultimately controls infection. The study of virus-encoded cell death receptors, pathogen sensors, IFNRs, Ag-specific death suppressor mutants brought RIP3 necrosis to light, re- TCR activation, and genotoxic stress. Necrosis leads vealing interdependencies fostered by a pathogen–host arms to cell leakage and acts as a “trap door,” eliminating cells race centered on cell death measures and countermeasures (5). that cannot die by apoptosis because of the elaboration of Based on the variety of strategies that have been observed, cell Downloaded from pathogen-encoded caspase inhibitors. Necrotic signaling death suppressors are crucial to the pathogenesis of all large requires RIP3 binding to one of three partners—RIP1, DNA viruses (2, 3, 5, 8, 9). Because cell death is triggered by DAI, or TRIF—via a common RIP homotypic inter- pre-existing cellular machinery, dysregulation can inadvertently action motif. Once activated, RIP3 kinase targets the kill cells and cause inflammatory disease, even in the absence of infection (7). The distribution of these pathways in all somatic

pseudokinase mixed lineage kinase domain-like to drive http://www.jimmunol.org/ cells opens possible routes to improve host resistance to natural cell lysis. Although necrotic and apoptotic death can pathogens, as well as to prevent infection of novel biothreat enhance T cell cross-priming during infection, mice agents. This review provides a perspective on recent advances in that lack these extrinsic programmed cell death path- RIP3 necrosis. The intention is to highlight triggers and al- ways are able to produce Ag-speciﬁc T cells and control ternate pathways of extrinsic cell death where therapeutic in- viral infection. The entwined relationship of apoptosis tervention might improve innate resistance to infection or drive and necrosis evolved in response to pathogen-encoded better cross-presentation during vaccination, without risking suppressors to support host defense and contribute to increased inﬂammatory disease (10). The derivation of viable,

inflammation. The Journal of Immunology,2014,192: fertile, and immunocompetent mice with combined deficiency by guest on September 23, 2021 2019–2026. in Casp8 and RIP3 (11) dismisses any key role for Casp8- regulated pathways in development, but it certainly raises im- egulated cell death is a potent arm of host defense (1– portant questions as to how apoptosis, as well as necrosis, con- 4), involving alternate strategies that evolved with tributes to the function of the immune system. animals to counteract pathogen-encoded cell death R Alternate Casp8-apoptosis and RIP3-necrosis pathways suppressors (3, 5). Intrinsic (mitochondrial) apoptosis is nec- essary for development (6), whereas extrinsic apoptosis and To set the stage for discussing the current understanding of programmed necrosis play out as alternate innate immune RIP3 kinase in host defense, it is important to consider the countermeasures to control infection (3, 5, 7). Although mech- crucial role that TNF-mediated signal transduction has played anistically distinct from Casp8-mediated extrinsic apoptosis, re- in the elaboration of alternate cytoprotective and cytotoxic ceptor interacting protein kinase (RIP)3 necrosis similarly pathways (1, 12). Three distinct outcomes of signal transduc- eliminates infected cells prior to release of viral progeny, tion via the TNF death receptor, TNFR1, are recognized: cyto- halting infection and triggering an inflammatory response (7). kine activation, extrinsic apoptosis, and programmed necrosis. Importantly, extrinsic apoptosis and necrotic cell death ma- These converge on death domain (DD) signaling that is or- chinery is distributed in all somatic cells. These pathways chestrated via the adaptor FADD in complex with Casp8 and reduce the burden of infection while also producing cell de- specific inhibitor, FLIP (12, 13) (Fig. 1). Pathogen sensors,

*Department of Microbiology and Immunology, Emory University School of Medicine, Emory University School of Medicine, Atlanta, GA 30322. E-mail address: mocarski@ Atlanta, GA 30322; †Emory Vaccine Center, Emory University School of Medicine, emory.edu Atlanta, GA 30322; and ‡Department of Molecular Biosciences, Institute for Cellular Abbreviations used in this article: DAI, DNA-dependent activator of IRF; DC, dendritic and Molecular Biology, University of Texas at Austin, Austin, TX 78712 cell; DD, death domain; DED, death effector domain; HCMV, human CMV; MCMV, Received for publication October 2, 2013. Accepted for publication December 20, 2013. murine CMV; MLKL, mixed lineage kinase domain-like; RHIM, receptor interacting protein kinase homotypic interaction motif; RIP, receptor interacting protein kinase; This work was supported by National Institutes of Health Grants R01 AI030363 vFLIP, viral FLIP; vICA, viral inhibitor of Casp8 activation; vIRA, viral inhibitor of and AI020211 to E.S.M., National Institutes of Health Grant T32GM008169 and receptor interacting protein kinase activation; WT, wild-type. an Achievement Rewards for College Scientists Fellowship to D.L.-R., National Insti- tutes of Health Grant OD012198 to W.J.K., and start-up funds from the University of Ó Texas at Austin and the Cancer Prevention Research Institute of Texas to J.W.U. Copyright 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 Address correspondence and reprint requests to Prof. Edward S. Mocarski, Department of Microbiology and Immunology, Emory Vaccine Center, 1462 Clifton Road NE,

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302426 2020 BRIEF REVIEWS: IMMUNE IMPLICATIONS OF RIP3 NECROSIS

IFNs, TCRs, and genotoxic stress all trigger analogous out- well as necroptosis, first emerged in studies of TNFR1 DD comes. Insights from TNFR DD signaling and identification signaling (22, 35, 36). Necroptosis is triggered when Casp8 of virus-encoded cell death suppressors using TNF-based becomes compromised during death signal transduction. In assays (14–16) has brought an appreciation of core cell these settings, RIP1 functions as both a RIP homotypic inter- death machinery operating as an integrated pathogen sensor action motif (RHIM)-dependent adaptor and a protein kinase system (5). In line with the view that extrinsic death came into to phosphorylate RIP3 (37–39), a partnership that results in existence to support host defense, both TNF antagonist im- formation of an amyloid-like complex (40). RIP3 kinase munotherapy (17) and genetic linkage studies (18) show that undergoes autophosphorylation and subsequently activates TNF signaling contributes as a redundant factor in host de- a target protein, mixed lineage kinase domain-like (MLKL), fense, like many other innate immune mechanisms. A goal of by phosphorylating key amino acids (7, 41, 42). The final steps this review is to highlight the growing evidence that TNF in this pathway involve the formation of an MLKL homotrimer opened the awareness to a broadly distributed innate cell that translocates to the plasma membrane to mediate Ca2+ influx death system able to prevent infection. via a transient receptor potential melastatin related 7 channel TNF family death receptors. TNFR1, as well as the Fas/CD95 (43). A similar RIP3–MLKL axis (28) is apparently shared by and TRAIL death receptors, control NF-kB activation, extrinsic the three pathways leading to RIP3 necrosis, whether RIP1 apoptosis, and programmed necrosis by DD signal transduction, dependent or RIP1 independent (Fig. 2). functioning in collaboration with death effector domain (DED) Pathogen sensors. Pathogen recognition receptors trigger NF-kB interactions (6) mediated via a critical complex consisting of and IRF3/IRF7 (44–46), activating production of IFN and Downloaded from Casp8, FLIP, FADD, and RIP1 (denoted “Complex IIB” down- other cytokines (47, 48). These sensors regulate alternate ac- stream of TNFR1 signal transduction) (19) and known as the tivation of cytokines or cell death in a manner analogous to “Necrosome” or “Ripoptosome” complex (3, 12, 13, 20, 21) TNF family death receptor signaling (3, 49), subject to mod- (Fig. 1). This cytosolic complex maintains control over alternate ulation by virus-encoded cell death suppressors (3, 23). RIP1– death outcomes downstream of TNF family death receptors RIP3 necroptosis (5, 7, 50) occurs downstream of TLR signaling (22), while also metering RIP1-enhanced induction of NF-kB (27, 28, 51), as well as via retinoic acid–inducible gene 1 or http://www.jimmunol.org/ (19) and RIP1 kinase–dependent programmed necrosis, also melanoma differentiation-associated protein 5 dsRNA helicase called necroptosis (3, 5, 12, 22, 23). RIP1 kinase–dependent enzymes (52, 53). Similar signaling also lies downstream of necroptosis is blocked by small molecule drugs, the necrostatins seemingly distinct pathogen response categories, including (24). Cell death triggered by death receptors, pathogen sensors genotoxic stress (34), IFN activation (31), Ag-dependent ac- (25–28), IFNs (29–31), Ag-specific TCR engagement (32, 33), tivation of T cells (32, 33), or infection with viruses, such as or genotoxic stress (34) is regulated by heterodimeric Casp8-FLIP vaccinia (37, 54), murine CMV (MCMV) (3, 25, 26), and within this core complex, preventing Casp8 self-activation and reovirus (55). In addition to RIP1, two RHIM-containing

extrinsic apoptosis (12, 13), while allowing sufﬁcient basal pro- adaptors are involved in activating RIP3: DNA-dependent ac- by guest on September 23, 2021 teaseactivitytosuppressnecrosis(3,12,13,20,21).Theability tivator of IRFs (DAI; also called ZBP1 or DLM1) (25) and of this core Casp8 complex to prevent extrinsic apoptosis, as TRIF (28), the key TLR3- and TLR4-signaling adaptor (Fig. 2).

FIGURE 1. Regulation of extrinsic apoptosis and RIP3 necrosis by a “Necrosome” or “Ripoptosome” complex. Cytoprotection (left panel). Signal transduction via death receptors (e.g., TNF) (37–39), pathogen sensors (e.g., TLR3 signaling) (27, 51), TCR activation (32, 33), or intracellular genotoxic stress (34) supports FADD association with the FLIP–Casp8 heterodimer via DED, as well as RIP1 via DD interaction. RIP1 orchestrates recruitment of RIP3 via an RHIM (red rectangle). The FLIP–Casp8 association prevents self-cleavage activation of Casp8 and maintains sufficient basal protease activity to prevent necroptosis, as well. E3 ubiquitin ligases cIAP1/cIAP2 or linear ubiquitination complex also prevent necroptosis by maintaining K63 or linear polyubiquitination (Ub–Ub) of RIP1 and other targets (34, 101, 102). Activation of necroptosis (right panel). When Casp8 activity is blocked by an inhibitor or E3 ubiquitin ligases are compromised (red “X”) by a mimetic of second mitochondria-derived activator of caspases (SMAC), RIP3 kinase autophosphorylates at S277 and targets MLKL (42) for phosphorylation at T357 and S358 (41). These modifications drive trimerization of MLKL and membrane disruption associated with Ca2+ influx via a transient receptor potential melastatin related 7–dependent plasma membrane channel (43). Deubiquitinase (DUB) activity removes polyubiquitin chains in the presence of SMAC mimetic, sensitizing to necrosis when Casp8 activity is compromised. The Journal of Immunology 2021

signaling. It forms as a result of pathogen alarm and control mechanisms as diverse as IFNs, genotoxic stress, and Ag activation of lymphocytes. This places the core Casp8–FADD– FLIP complex (27, 32, 34, 37–39, 51, 52) in the role of a mammalian pathogen supersensor (28).

Purpose of RIP3 necrosis DNA virus–encoded cell death suppressors are crucial to pathogenesis of viral infection and disease progression (1–4). These functions have contributed to dissection of extrinsic death pathways (3, 5, 7). Initially, apoptosis-prone L929 (59) and necrosis-prone L-M variant cell line (60) led to assays (61) that allowed for the identification of adenovirus-encoded cell death suppressors (14). Poxviruses and herpesviruses pro- vided the first examples of DED-containing Casp8 suppressors, so-called “viral FLIPS” [(v)FLIPs] (62, 63), opening the way toward understanding the prosurvival role of NF-kB(64),as well as the consequences of cellular FLIP-Casp8 heterodi- Downloaded from merization (12). Cowpox caspase and serine protease inhibitor, CrmA, was crucial in characterizing necrosis as a caspase- FIGURE 2. Three distinct RHIM complexes trigger RIP3 necrosis. RIP1– RIP3 necroptosis, first characterized downstream of death receptor activation independent pathway triggered by TNF under conditions via RIP1–RIP3 complex formation (37–39), is also induced by pathogen that prevent Casp8-dependent extrinsic apoptosis (65). The sensor (e.g., TLR2, TLR4, TLR5, or TLR9 MyD88-dependent signaling) concept that RIP3 necrosis may be a host countermeasure (27, 28), TCR activation (32, 33), intracellular genotoxic stress (34), or against viruses encoding caspase inhibitors (3, 9, 33) has http://www.jimmunol.org/ vaccinia virus infection (37). Virus-induced DAI–RIP3 necrosis (3, 25, 26) is been refined with the demonstration that the highly specific activated by MCMV M45 mutant virus infection. TRIF–RIP3-dependent CMV-encoded viral inhibitor of Casp8 activation (vICA) necrosis in fibroblasts is activated by TLR3 or TLR4 ligands (27, 28). RIP3 predisposes to RIP3 necrosis (11). Consistent with this un- complexes with RIP1, DAI, or TRIF depend on RHIM-dependent complex formation that activates RIP3 kinase–dependent modification of MLKL (7, derstanding, TNF-induced necroptosis makes a striking contri- 41, 42) (see Fig. 1). MCMV M45–encoded vIRA functions as a dominant bution to host defense against the poxvirus and vaccinia in mice RHIM-inhibitor preventing RIP3 association with RIP1, DAI, or TRIF. (37, 54) where a virus-encoded inhibitor related to CrmA likely unleashes the pathway.

Wild-type (WT) MCMV is insensitive to RIP3 necrosis; by guest on September 23, 2021 RIP3 directly engages the pathogen sensor DAI independent however, MCMV-encoded M45 mutant viruses that are de- of RIP1 when cells or mice are infected with a mutant ficient in vIRA induce necrosis within a few hours of invading MCMV strain that lacks the M45-encoded viral inhibitor of cells (3, 25, 26) via a DAI–RIP3 complex. Curiously, math- RIP activation (vIRA) (25). Furthermore, RIP3 engages TRIF ematical models of MCMV vIRA and vICA function (66) downstream of TLR3 in both RIP1-dependent and RIP1- have completely missed the mark (11, 20). vIRA acts as a vi- independent pathways (27, 28, 51). DAI and TRIF engage rion protein (67) to block RHIM-dependent signaling (3, 25, in RHIM-dependent interactions that converge on RIP3 kinase 26) upon delivery to cells during initial penetration (67–70). (5). The necrotic death mediated by DAI-RIP3 (25, 26) and vIRA-deficient virus fails to gain a foothold in the host be- TRIF-RIP3 (28) may proceed independent of RIP1, but cause infection halts as a result of the elimination of virus- nevertheless follow similar parameters (37–39) and converge exposed cells prior to the production of progeny virus. Two on MLKL (28, 41, 42, 56, 57) (Fig. 1). Thus, a RIP3 necrosis key issues remain to be fully addressed: whether MCMV- “trap door” lies downstream of innate immune signaling, and cell encoded vICA suppression of apoptosis is responsible for death may be triggered either independent of or dependent on unleashing DAI–RIP3 necrosis under natural infection con- death receptors and RIP1 kinase activity (3, 5, 7), through the ditions in the host animal (3, 28) and how the core Casp8 various pathogen-related signaling events depicted in Fig. 2. complex communicates with RIP3 kinase without the benefit IFNs. Type I (IFN-a and IFN-b) or type II (IFN-g)IFNsact of the adaptor RIP1 (Fig. 1). on receptors (INFabRorIFNgR, respectively) to trigger JAK- Human CMV (HCMV) and MCMV both encode vICA STAT signal transduction and mediate antiviral and immu- (71) and block Casp8 apoptosis, a viral strategy that is par- nomodulatory outcomes. IFNs also induce cell death (58) ticularly important during infection of macrophages (72). analogous to death receptors and pathogen sensors (3, 49), HCMV has a homolog of M45 (73), called UL45, but this but it is carried out by distinct JAK-STAT–signaling cascades. fails to suppress cell death (74, 75). The parallels of vICA Recent studies implicate both IFN-b (29) and IFN-g (30) in function aside, most of the immunomodulators encoded by RIP1-dependent cell death with characteristics of RIP3 MCMV and HCMV act independently on conserved host necrosis. Activation of cell death by IFN-g requires JAK- defense pathways. HCMV infection blocks necrosis (S. Omoto STAT function, as well as RIP1 and RIP3 (31). The impact and E.S. Mocarski, manuscript in preparation); however, the of either FADD or caspase compromise produces a picture nature of the HCMV-encoded necrosis inhibitor remains to that points to the same core cytosolic Casp8–FADD–FLIP– be determined. Based on early experimental data (3, 9), some RIP1 “Ripoptosome” complex (Fig. 1). This complex forms vFLIPs may act as suppressors of necrotic death. RIP3 necrosis in response to intracellular pathogens as well as death receptor plays out in humans, as well as mice, although humans encode 2022 BRIEF REVIEWS: IMMUNE IMPLICATIONS OF RIP3 NECROSIS two self-processing caspases (Casp8 and Casp10), whereas rodents midgestational death in mice. Casp8-FLIP association within have only Casp8. Nevertheless, primary human peripheral blood the core complex (Fig. 1) blocks RIP3 necrosis (20), potentially cells retain the capacity for necroptosis under experimental con- targeting RIP1, RIP3, or some component of polyubiquitylation/ ditions that parallel what is known in mice (76). deubiquitylation machinery (Fig. 1); however, the precise target The increased susceptibility of RIP3-deficient mice to (s) of basal caspase activity that prevents necrosis remains to be vaccinia infection (37) stands in striking contrast to natural clarified. Casp8-deficient humans survive development but ex- infection with MCMV, in which vIRA sustains infection by hibit immunodeficiency (82), a phenotype that is remarkably preventing DAI-RIP3 necrosis (25) (Fig. 2) but where elim- similar to T cell–specific disruption of either Casp8 (32, 83) or ination of the RIP3 pathways does not alter WT virus path- FADD (84) in mice where T cells die by necroptosis upon ogenesis or control (26). Thus, RIP3 necrosis is a mechanism TCR activation (32, 84). The ability of TCR to trigger RIP3 of host defense that threatens virus-infected cells, making the necrosis indicates that the CARMA1–BCL10–MALT1 com- dialogue between vIRA and RIP3 crucial in both immuno- plex that normally activates NF-kB also influences the core competent (26, 69), as well as in immunodeficient, mice “Ripoptosome” complex or, alternatively, contributes to in- lacking NK, T, and B cell functions (25, 26, 67). The need creased production of TNF, followed by TNFR1-induced for vIRA is reversed in RIP3- and DAI-deficient mice (25) necroptosis (Fig. 2). where the mutant virus replicates and disseminates. Thus, All settings in mice in which deficiency of Casp8 (11, 20), RIP3 necrosis operates within infected cells. RIP3 does not FADD, or FLIP (21) has been rescued by eliminating RIP3 make an apparent contribution to the function of immune produce viable and fertile mice that exhibit lymphoid hy- Downloaded from cells that respond to and control infection. RIP3 partner DAI perplasia accompanied by the accumulation of an abnormal has the capacity to trigger RHIM- and RIP3-dependent IFN B220+ T cell population as they age (85). This phenotype activation in mouse and human cells (77, 78), although nei- aligns with the importance of Fas-dependent extrinsic apo- 2 2 ther NF-kB nor IFN contributes to virus-induced necrosis ptosis in the homeostatic turnover of T cells. tCasp8 / 2 2 2 2 (25). DAI-dependent IFN activation can be suppressed by Rip3 / or tFaddddRip3 / (84) mice phenocopy this defect,

MCMV-encoded vIRA (77, 79); however, the contribution of revealing a requirement for Casp8 function to eliminate excess http://www.jimmunol.org/ this one pathogen sensor in dictating levels of NF-kB and T cells that is independent of RIP3. Curiously, humans with IRF3 activation during natural infection in the host has not Casp10 deficiency exhibit an autoimmune lymphoprolifer- been gauged with any accuracy. Parenthetically, DAI certainly ative syndrome characteristic of Fas signaling deficiency (82) contributes to HCMV virion–induced IFN response in cell that also matches the phenotype of Fas signaling deficiency in culture (80). With MCMV infection, RIP3 necrosis becomes mice. subdued, enabling virus infection and dissemination to pro- Other than lymphoid hyperplasia that develops with age, 2 2 2 2 ceed (25, 26, 68). In aggregate, the elaboration of a potent Casp8 / Rip3 / mice exhibit none of the severe develop-

suppressor by MCMV reveals that RIP3 necrosis can com- mental defects, homeostatic collapse, or increased inflamma- by guest on September 23, 2021 pletely arrest viral infection by killing off infected cells inde- tion that result from the disruption of either Casp8 or FADD pendent of other immune mechanisms, as well as the particular in specific tissues (49, 52, 86–100). Thus, RIP3 necrotic inoculation route. It would be a remarkable feat to harness RIP3 death and unleashed inflammation are both consequences of by therapeutic intervention to confer pathogen-independent compromised Casp8 function. Compromise in E3 ubiquitin resistance to a wide range of infectious agents, such as those that ligases cIAP1 and cIAP2 or in the SHARPIN component of pose a potential biothreat. the linear ubiquitination complex results in similar inflam- Although potentiators of RIP3 necrosis have not been in- matory outcomes (34, 101, 102), and it was the topic of a vestigated, necrotic death is experimentally blocked by recently recent review (103). Thus, the interdependency of Casp8 and described small molecule RIP3 kinase inhibitors (28) that act RIP3 pathways, which evolved for host defense, leads to regardless of whether triggered by RIP1–RIP3, DAI–RIP3, or serious developmental, homeostatic, and inflammatory com- TRIF–RIP3 complex formation. Such inhibitors promise to plications. Disparate observations in the fields of immunology expand our understanding of RIP3 kinase in necrotic death, and cell and development biology, as well as in signal trans- similar to the powerful impact that necrostatins have had on duction, center on dysregulation of a core “Ripoptosome” defining the specific role of RIP1 kinase activity in necroptosis complex that can sidetrack cell cycle progression, NF-kB ac- (22). tivation, autophagy, cell adhesion and migration, and inflammation (12, 32, 33, 49). The picture reveals a striking RIP3 necrosis underlying developmental failure and inflammation system-wide role for Casp8 in silencing RIP3-dependent Host defense mechanisms involving immune cells that protect pathways to prevent inflammatory damage and disease from infection through innate and adaptive mechanisms have throughout development and during life (7). the potential to trigger immunopathology (10). Death pathways emanating from the core Casp8 complex are known to RIP3 necrosis contribution to host defense undermine development and tissue homeostasis by unleash- Despite deficiency in extrinsic apoptosis and RIP3 necrosis, 2 2 2 2 ing RIP3 necrosis and inflammation (3, 5, 12, 49). When Casp8 / Rip3 / mice can control viral infection like WT germline Casp8 or FADD deficiency is rescued by elimination or RIP3-deficient mice (11), mounting CD8 T cell responses of RIP3 (11, 20) or RIP1 (81), respectively, RIP1–RIP3 to control acute MCMV infection (D. Livingston-Rosanoff necroptosis emerges as a specific risk when the Casp8 complex and E.S. Mocarski, manuscript in preparation) that compare becomes compromised during development (3, 5, 12). Al- with matched C57BL/6 mice (104, 105). In addition, 2 2 2 2 2 2 though RIP3 engages DAI (25) and TRIF (28) as alternatives tCasp8 / Rip3 / (32, 83) and tFaddddRip3 / (84) mice to RIP3, neither of these RHIM adaptors contributes to retain full immune control over the RNA viruses lymphocytic The Journal of Immunology 2023

2 2 choriomeningitis virus and mouse hepatitis virus. Casp8 / raises a very important question about the contribution of 2 2 Rip3 / mice support MCMV-specific CD8 T cell expan- extrinsic cell death to the immune response in the WT host. sion, contraction, and recall like WT controls, including This question is important on several levels: the basis of vaccine characteristic memory inflation and complete protection from immunogenicity rests on empirical comparisons to natural secondary challenge. Thus, extrinsic death pathways are re- virus infection (115), little is known about the independent dundant, in a pattern that also characterizes other immune contribution of innate immune cell death independent of 2 2 2 2 mechanisms (10). Experiments with Casp8 / Rip3 / mice innate immune induction of cytokine production, and ex- showed that cytotoxicity, turnover of responding cells, perimental studies have long suggested a correlation between memory T cell maintenance and recall, as well as aspects of induction of cell death and immunogenicity (50, 107, 108), the cellular immune response to virus infection that interface although this has not been addressed in hosts that are deficient with other immune and nonimmune cell types, can proceed in major cell death pathways or with pathogens that are completely independent of extrinsic apoptosis. This comes as specifically susceptible to apoptotic or necrotic death. Ex- a surprise given the range of lymphocytes, macrophages, and trinsic apoptosis and programmed necrosis certainly influence DCs that is known to collude in control of viral infection and immune response parameters toward virus-infected cells in the repeated implication of death receptors, as well as path- infection models (50, 107, 108). In the setting of systemic ogen sensors and other signaling pathways, that trigger ex- MCMV infection, where cross-presentation dominates CD8 trinsic cell death in the overall immune response to infection. T cell priming (109) and relies on the CD8a subset of DCs

Most surprising of all is that elimination of extrinsic cell death (116), the impact of particular cell death pathways on CD8 Downloaded from does not impact the intensity of the Ag-speciﬁc CD8 T cell T cell immunity remains to be established. This area has response, which is dependent on APCs that present viral relevance because CMVs have potential as vaccine vectors to peptides by cross-presentation (106). In line with other protect against pathogens, such as HIV (117–120). In natural infections (50, 107, 108), the immune response to MCMV infection, viral load is a major driver of adaptive immunity. within WT mice is inﬂuenced by levels of cross-presentation Attenuated or replication-defective viral vectors typically drive that depend on dying virus–infected cells for a protective CD8 a weaker T cell response that may exhibit different qualitative http://www.jimmunol.org/ T cell response (109). This occurs via immunoproteasome- parameters than the original viral pathogen (115). This has dependent APC function (110, 111) that counters virus- triggered a growing literature on the topic of rational vaccine mediated MHC class I downregulation in infected APCs vector design (121), as well as the search for vectors that have 2 2 2 2 (112). Casp8 / Rip3 / mice probably depend on intrinsic, the potential to deliver supernatural immunogenicity, such as Bcl2 family member Bim-dependent apoptosis (6) for purposes observed with rhesus macaque CMV (120). Contributions of of lymphocyte contraction, as well as for turnover in the an- cross-presentation to CD8 T cell priming can be addressed tiviral CD8 T cell response, because there is no other known by disrupting either MCMV (109) or mouse (116) genetic 2/2 2/2

pathway to support cross-presentation (108). Casp8 Rip3 determinants, such as virus-encoded cell death suppressors, or by guest on September 23, 2021 mice are able to support memory inflation that accompanies the extrinsic apoptosis and programmed necrosis pathways latent infection, a pathway that depends on direct Ag presen- that they target (16). tation (113), as well as CD4 T cell function (114). The ability Proapoptotic vICA (121) and pronecrotic vIRA (26) mu- 2 2 2 2 of Casp8 / Rip3 / mice to mount diverse innate and adap- tant MCMV induce premature Casp8 apoptosis (121, 122) tive immune responses in the absence of extrinsic death ma- and RIP3-dependent necrosis (25, 26), cutting short infection chinery indicates that Fas, other death receptors, or any innate (16). Replication levels of vICA- and vIRA-deficient viruses 2 2 2 2 signaling via the “Ripoptosome” complex is dispensable for a become normalized in Casp8 / Rip3 / (double knockout) cellular immune response that controls infection (84). mice due to the absence of the pathways that these cell death suppressors target. Systemic inoculation (123) delivers suffi- Immunogenicity of proapoptotic and pronecrotic viruses cient virus to trigger a cross-presentation–mediated response, The remarkable ability of mice lacking Casp8 and RIP3 even when a replication-defective virus is used, although peak pathways to mount a protective CD8 T cell immune response antiviral responses are lower (109). WT MCMV produces

FIGURE 3. Model: viral Ag load and cell death pathways collaborate in cross-presentation to drive CD8 T cell immunity during infection. Model derived from studies on the impact of apoptotic and necrotic cell death pathways on cross-presentation in the CD8 T cell response (50, 107, 108), as well as developing understanding of MCMV immune response parameters. Relative peak viral load (shaded gray circles) at day 3 postinfection and peak CD8 T cell response at day 7–10 postinfection (multicolored circles) with WT MCMV (K181 strain), proapoptotic mutant ΔM36, or pronecrotic mutant M45mutRHIM. The benefit of enhanced cross-presentation from either proapoptotic or pronecrotic viruses is depicted by the dashed gray circles. DKO, double knockout. 2024 BRIEF REVIEWS: IMMUNE IMPLICATIONS OF RIP3 NECROSIS sizeable virus loads in spleens, livers, and lungs of WT and 5. Kaiser, W. J., J. W. Upton, and E. S. Mocarski. 2013. Viral modulation of programmed necrosis. Curr. Opin. 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