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Cited by 1,176Immunotherapy and Immune ResponsesImmune Response and InflammationCell death mechanisms and regulation

Immunogenic and tolerogenic cell death

Open access
Green, Douglas R., Ferguson, Thomas, Zitvogel, Laurence, Kroemer, Guido·2009·Nature Reviews Immunology
DOI 10.1038/nri2545PMC PMC2818721
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Abstract

The immune system is routinely exposed to dead cells during normal cell turnover, injury and infection. Mechanisms must exist to discriminate between different forms of cell death to correctly eliminate pathogens and promote healing while avoiding responses to self, which can result in autoimmunity. However, an effective immune response against host tissue is often needed to eliminate tumours following treatment with chemotherapeutic agents that trigger tumour cell death. Consequently, a central problem in immunology is to understand how the immune system determines whether cell death is immunogenic, tolerogenic or 'silent'.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that the immune outcome of cell death is not determined by a simple apoptosis-versus-necrosis dichotomy, but by a combination of cell type, death pathway, stress history, released or exposed DAMPs, phagocyte type, and anatomical location. It synthesizes evidence that dying cells can drive immunity, tolerance, or silence, with implications for cancer therapy, infection, autoimmunity, and tissue injury.

Key findings

  • The classical view that apoptosis is tolerogenic and necrosis is immunogenic is challenged: apoptotic tumor cells can prime immune responses, while necrotic cells can sometimes be less immunogenic than certain apoptotic cells.
  • Immunogenicity depends on multiple interacting factors, including intrinsic antigenicity, prior activation or stress, the death inducer, caspase activity, autophagy, and the availability of responsive immune cells.
  • Specific signals shape outcomes: calreticulin–ERp57 exposure and HSPs can promote uptake and immunogenicity; HMGB1 release is required in some immunogenic death models; ATP, uric acid, SAP130–Mincle, and a CLEC9A ligand are implicated in immune sensing of dead cells.
  • Tolerance can be actively induced by apoptotic cells through mechanisms such as helpless CD8+ T cells producing TRAIL, splenic CD8α+ dendritic cells, intravenous versus subcutaneous routes, TGFβ/IL-10 release, and regulatory T cell generation; IL-6 can shift this toward TH17 responses.
  • The paper notes that in humans roughly one million cells die per second during normal turnover, usually without autoreactivity.

Methods

  • This is a review article, not a primary experimental study; it synthesizes published literature and conceptual models.
  • It draws on experimental systems described in the paper’s boxes, including tumor vaccination/challenge assays, CTL priming assays, delayed-type hypersensitivity and tolerance assays, dendritic cell adoptive transfer, and knockout or blocking studies.
  • The main analysis is a conceptual framework linking cell death modalities, DAMPs, phagocyte receptors, caspase/autophagy pathways, and immune outcomes.

Limitations

  • The authors state that they provide only a snapshot of a rapidly evolving field and that the consequences of dying cells for every aspect of immunity are not fully understood.
  • The text makes evident that several mechanisms remain unresolved, including the identity of the CLEC9A ligand, the molecular basis of activation-dependent immune stimulation, the role of lysophosphatidylcholine in immunogenic death, and whether certain cytokines are required for responses to dying cells.
  • The review cautions that some evidence is controversial or based on unpublished observations, and that TLR involvement can be confounded by possible ligand contamination; it also notes that in vivo immunogenicity data for pyroptosis are lacking.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nri2545

Cites

126 of 126 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 133 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    DAMPs released from dying cells induce immune responses to cellular antigens whether the cell is a tumor cell, autologous tissue or infected with a pathogen.

    “DAMPs are released from dying cells and induce immune responses to cellular antigens whether the cell is a tumor cell, autologous tissue or infected with a pathogen.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Gaipl, U. S. et al. Clearance deficiency and systemic lupus erythematosus (SLE). J. Autoimmun. 28, 114–121 (2007). source

      Not checked in the free run.

  • Premisecitation

    Activated but not resting γ-irradiated peripheral blood mononuclear cells can induce maturation markers and pro-inflammatory cytokine secretion by DCs in vitro.

    “Activated but not resting γ-irradiated peripheral blood mononuclear cells can induce the expression of maturation markers (such as CD80, CD83 and CD86) and the secretion of pro-inflammatory cytokines by DCs in vitro29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nature Rev. Immunol. 8, 59–73 (2008). source

      Not checked in the free run.

  • Premisecitation

    Autoimmunity is observed in mice whose phagocytes lack G2A, a receptor required for response to lysophosphatidylcholine.

    “However, autoimmunity has been observed in mice in which phagocytes lack the G-protein coupled receptor G2A41, which is required for the response to lysophosphatidylcholine 42”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Lauber, K. et al. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113, 717–730 (2003). source

      Not checked in the free run.

    • cites [42] Le, L. Q. et al. Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome. Immunity 14, 561–571 (2001). source

      Not checked in the free run.

  • Interpretationcitation

    Activated apoptotic cells may possess endogenous adjuvant properties.

    “This suggests that activated apoptotic cells may possess endogenous adjuvant properties.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    The nature of the immune response to cell death depends on what cell dies, where it dies, how it dies, who eats it, and when associated antigen is recognized.

    “Therefore, the nature of the immune response to cell death depends on the following considerations: what cell dies, where it dies, how it dies, who eats it, and when (or if) associated antigen has been or will be recognized.”
    Quote in the paperSubstantial claim
  • May combine two claims. 35
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Premisecitation

    Uric acid can function as a DAMP by activating the inflammasome in APCs, stimulating production of IL-1β, IL-18 and IL-33 via caspase-1.

    “Nucleotide products such as uric acid can also function as DAMPs, presumably by activating the inflammasome in APC, thereby stimulating the production of inflammatory cytokines such as interleukin-1β (IL-1β), IL-18 and IL-33, the secretion of which depends on the inflammasome-mediated activation of caspase-145,46.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Hanley, P. J. et al. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages. Proc. Natl Acad. Sci. USA 101, 9479–9484 (2004). source

      Not checked in the free run.

    • cites [46] Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CRT exposure strongly correlates with immunogenicity; anthracyclin-treated dying tumor cells exposing CRT can vaccinate against cancer and lose immunogenicity upon CRT depletion or neutralization.

    “This feature strongly correlates with immunogenicity, and anthracyclin-treated dying tumor cells that expose CRT can be used to vaccinate against cancer, yet lose their immunogenicity upon siRNA-mediated depletion or antibody-mediated neutralization of CRT.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    Physiological apoptosis is intrinsically tolerogenic, whereas pathological necrosis is inherently immunogenic and elicits inflammatory reactions.

    “The second approach is based on the theory that distinct types of cell death (Box 2) induce different types of immune responses: that physiological cell death (apoptosis) is intrinsically tolerogenic, whereas pathological cell death (necrosis) is inherently immunogenic and elicits inflammatory reactions5.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNA damage of transformed cells induces expression of NKG2D ligands, which act on NKG2D expressed by NK cells and CTL.

    “DNA damage of transformed cells induces the expression of surface proteins such as natural-killer group 2, member D (NKG2D) ligands, which act on NGK2D expressed by natural killer (NK) cells and CTL31.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Herndon, J. M., Stuart, P. M. & Ferguson, T. A. Peripheral deletion of antigen-specific T cells leads to long-term tolerance mediated by CD8+ cytotoxic cells. J. Immunol. 174, 4098–4104 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The timing of dead-cell uptake may be important: cells dying at the height of an immune response may promote immunity, whereas cells dying as the response wanes may be tolerogenic.

    “Thus, the timing of dead-cell uptake may be important; cells that die at the height of an immune response may promote immunity, whereas cells that die as the response wanes may be tolerogenic.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    ATP released from dying cells activates macrophages and may be required for immunogenicity of dying tumor cells.

    “Indeed, ATP, which is released from dying cells and activates macrophages 44, may also be required for the immunogenicity of dying tumor cells (L.Z. and G.K., unpublished observations).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Koizumi, S. et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 1091–1095 (2007). source

      Not checked in the free run.

    • cites L.Z. and G.K., unpublished observations

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The immune system must distinguish among different forms of cell death to eliminate pathogens and promote healing without responding to self.

    “Mechanisms must exist to discriminate between different forms of cell death in order to correctly eliminate pathogens and promote healing while avoiding responses to self, which can result in autoimmunity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    There are subcategories of cell death, such as immunogenic versus non-immunogenic apoptosis, and subtle differences in cell surface composition and secreted products determine whether death is immunogenic.

    “In an effort to reconcile these different data, it has been proposed that there are subcategories of cell death (such as immunogenic versus non-immunogenic apoptosis) and that subtle differences in the composition of the cell surface and/or in the products, which could include DAMPs, that are secreted by the dying cells determine whether the death of the cell is immunogenic or not7.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Dead cells that are shed from bodily surfaces have little or no influence on the host immune response, whereas those that are engulfed can affect it.

    “Those that are shed have little or no influence on the host immune response but those that are engulfed have the potential to affect it.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Dead cells are either shed from bodily surfaces or cleared by engulfment.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Recognition of PAMPs by immune cells dictates the difference between silent and immunogenic cell death.

    “The first approach is based on the theory that the recognition of pathogen-associated molecular patterns (PAMPs), such as bacterial cell wall components or viral RNA, by immune cells dictates the difference between silent cell death (which occurs in the absence of a pathogen) and immunogenic cell death (which is induced by a pathogen)1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Reed, J. C. Drug insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms. Nature Clin. Pract. Oncol. 3, 388–398 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cells dying by apoptosis can be vigorously immunogenic, whereas necrotic cells can be less immunogenic than cells undergoing an immunogenic form of apoptosis.

    “However, in-depth investigations have shown that cells dying by apoptosis can be vigorously immunogenic, whereas necrotic cells can be less immunogenic than cells undergoing an immunogenic form of apoptosis 2,6.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Medzhitov, R. & Janeway, C. A. Jr. Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300 (2002). source

      Not checked in the free run.

    • cites [6] Thompson, C. B. Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–1462 (1995). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    For cell death to be immunogenic, it must release DAMPs to stimulate immune cells.

    “Therefore, it has been proposed that for cell death to be immunogenic, it must release DAMPs to stimulate immune cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Absorbing CRT to live tumor cells does not suffice to render them immunogenic, meaning additional factors are essential for immunogenicity.

    “However, the absorbance of CRT to live tumor cells does not suffice to render them immunogenic 7, meaning that additional factors are essential for immunogenicity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    DAMPs released from or exposed at the surface of dying cells determine engulfment of apoptotic bodies, dendritic cell activation, antigen processing, dendritic cell maturation, and T cell activation.

    “Such damage-associated molecular patterns (DAMPs) released from or exposed at the surface of dying cells then determine the engulfment of apoptotic bodies, DC activation, antigen processing, DC maturation, and T cell activation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    If dying cells supplied the antigens that maintain peripheral tolerance, then parasites that induce cell death would be protected by the immune system, which is untenable.

    “If dying cells provide the antigens that sustain peripheral tolerance, then parasites that trigger cell death would be cosseted by the immune system, which is clearly untenable.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DC that engulf necrotic cells present antigen to both CD4+ and CD8+ T cells, whereas those that engulf apoptotic cells present antigen to CD8+ T cells but not CD4+ T cells.

    “DC that have engulfed necrotic cells present antigen to both CD4+ and CD8+ T cells, however those that engulf apoptotic cells present antigen to CD8+ T cells but not CD4+ T cells72.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD8+ T cells produce TRAIL upon re-exposure to antigen, which inhibits immunization for cell-mediated responses and mediates tolerance.

    “As a result, the CD8+ T cells produce TRAIL upon re-exposure to antigen, which acts to inhibit immunization for cell-mediated responses (that is, mediate tolerance).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Janssen, E. M. et al. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature 421, 852–856 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dying cells expose or release an unidentified DAMP recognized by CLEC9A on CD8α+ DC, which activates Syk kinase and cross-presentation of associated antigens on MHC class I.

    “Dying cells also expose or release another as yet unidentified DAMP which is recognized by a receptor, CLEC9A, present on CD8α+ DC 55. This activates Syk kinase and cross-presentation of associated antigens on class I MHC.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Yamasaki, S. et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nature Immunol. 9, 1179–1188 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The proposition that dying cells are always immunogenic is untenable because the potential for autoimmunity is readily apparent.

    “The alternative, that dying cells are always immunogenic, is equally untenable, as the potential for autoimmunity is readily apparent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Failure in autophagy blocks removal of apoptotic corpses and influences immunogenicity of cell death.

    “and therefore a failure in autophagy blocks the removal of apoptotic corpses and influences the immunogenicity of cell death.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Potential immunogenic signals from dying cells include surface-exposed proteins such as calreticulin and heat shock proteins, lipid moieties such as phosphatidylserine that flip to the outer leaflet, released proteins such as HMGB1, and extracellular nucleic acids and their degradation products (oligonucleotides, nucleotides, nucleosides, urate).

    “Potential immunogenic signals emanating from dying cells include proteins that appear at the surface of stressed and dying cells (such as calreticulin and heat shock proteins, HSPs), lipid moieties that flip from the inner plasma membrane leaflet to the outer leaflet (such as phosphatidylserine) 38,60, proteins that are released into the supernatant of cells (such as HMGB1) 51, as well as nucleic”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [38] Obeid, M. et al. Ecto-calreticulin in immunogenic chemotherapy. Immunol. Rev. 220, 22–34 (2007). source

      Not checked in the free run.

    • cites [60] Tenev, T., Ditzel, M., Zachariou, A. & Meier, P. The antiapoptotic activity of insect IAPs requires activation by an evolutionarily conserved mechanism. Cell Death Differ. 14, 1191–1201 (2007). source

      Not checked in the free run.

    • cites [51] Kazama, H. et al. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29, 21–32 (2008). This study 'connects the dots' from caspase activation to ROS production to modification of HMGB1 and to immune tolerance. source

      Not checked in the free run.

    • cites [43] Peter, C. et al. Migration to apoptotic “find-me” signals is mediated via the phagocyte receptor G2A. J. Biol. Chem. 283, 5296–5305 (2008). source

      Not checked in the free run.

    • cites [44] Koizumi, S. et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 1091–1095 (2007). source

      Not checked in the free run.

    • cites [45] Hanley, P. J. et al. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages. Proc. Natl Acad. Sci. USA 101, 9479–9484 (2004). source

      Not checked in the free run.

    • cites [105] Hedrick, S. M. The acquired immune system: a vantage from beneath. Immunity 21, 607–615 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Without licensing signal, activated helpless CTLs function as primary effector T cells but have a short lifespan or die via activation-induced cell death after subsequent antigen exposure.

    “Without this additional signal, the activated ‘helpless’ CTL function as primary effector T cells but with a short lifespan69 or die via activation-induced cell death following subsequent exposure to antigen70,71.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [69] Schoenberger, S. P., Toes, R. E., van der Voort, E. I., Offringa, R. & Melief, C. J. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393, 480–483 (1998). source

      Not checked in the free run.

    • cites [70] Sun, J. C. & Bevan, M. J. Defective CD8 T cell memory following acute infection without CD4 T cell help. Science 300, 339–342 (2003). source

      Not checked in the free run.

    • cites [71] Janssen, E. M. et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93 (2005). This studied characterizes the production of TRAIL following restimulation of helpless CTLs and defines its role both in killing the CTLs and inhibiting T cell responses. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy does not constitute an effector mechanism of cell death but often accompanies cell death.

    “Although autophagy does not constitute an effector mechanism of cell death61, it often accompanies cell death 62 (Box 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Obeid, M. et al. Calreticulin exposure is required for the immunogenicity of γ-irradiation and UVC light-induced apoptosis. Cell Death Differ. 14, 1848–1850 (2007). source

      Not checked in the free run.

    • cites [62] Kroemer, G. & Levine, B. Autophagic cell death: the story of a misnomer. Nature Rev. Mol. Cell Biol. 9, 1004–1010 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SAP130 is released by necrotic and late apoptotic cells and binds Mincle, an ITAM-coupled activating receptor mainly expressed by macrophages.

    “A recent study has identified spliceosome-associated protein 130 (SAP130), which is a component of small nuclear ribonucleoprotein, as another DAMP that is released by necrotic and late apoptotic cells 54. SAP130 specifically binds to macrophage-inducible C-type lectin (Mincle/Clec4e), which is an immunoreceptor tyrosine-based activation motif (ITAM)-coupled activating receptor that is mainly”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Depletion of HMGB1 from tumor cells undergoing immunogenic apoptosis abolishes their ability to induce T-cell priming or protect mice against tumor growth following vaccination, indicating HMGB1 is required for immunogenicity of cell death.

    “Depletion of HMGB1 from tumor cells undergoing immunogenic apoptosis (induced by anthracyclins, oxaliplatin or ionizing irradiation) abolishes their ability to induce T-cell priming or to protect mice against tumor growth following vaccination27, indicating that this DAMP is required for the immunogenicity of cell death.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Segal, N. H. et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 68, 889–892 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of caspases affects exposure of find-me signals, eat-me signals, secretion of DAMPs, and exposure of CRT on anthracyclin-treated cancer cells.

    “The inhibition of caspases affects the exposure of find-me signals 40, eat-me signals 40 (Box 4), and the secretion of DAMPs51 from dying cells, as well as the exposure of CRT on anthracyclin-treated cancer cells60.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [40] Panaretakis, T. et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ. 15, 1499–1509 (2008). source

      Not checked in the free run.

    • cites [51] Kazama, H. et al. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29, 21–32 (2008). This study 'connects the dots' from caspase activation to ROS production to modification of HMGB1 and to immune tolerance. source

      Not checked in the free run.

    • cites [60] Tenev, T., Ditzel, M., Zachariou, A. & Meier, P. The antiapoptotic activity of insect IAPs requires activation by an evolutionarily conserved mechanism. Cell Death Differ. 14, 1191–1201 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutralization of Mincle inhibits neutrophil recruitment and pro-inflammatory cytokine production after intraperitoneal injection of dead tumor cells, indicating a role for SAP130-Mincle in immunogenicity of dead cells in vivo.

    “Neutralization of Mincle with a specific antibody inhibited the recruitment of neutrophils and pro-inflammatory cytokine production following intraperitoneal injection of dead tumor cells54, indicating a role for SAP130–Mincle in the immunogenicity of dead cells in vivo.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tolerance induction by apoptotic cells depends on MHC class I molecules and involves immune suppression by CD8+ T cells.

    “Perhaps paradoxically, tolerance induction by apoptotic cells depends on MHC class I molecules and involves immune suppression by CD8+ T cells10,24,25.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Griffith, T. S., Yu, X., Herndon, J. M., Green, D. R. & Ferguson, T. A. CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance. Immunity 5, 7–16 (1996). This is an early paper showing that apoptotic cells induce tolerance to associated antigens. source

      Not checked in the free run.

    • cites [24] Schwarz, A. et al. Ultraviolet light-induced immune tolerance is mediated via the Fas/Fas-ligand system. J. Immunol. 160, 4262–4270 (1998). source

      Not checked in the free run.

    • cites [25] Heath, W. R. & Carbone, F. R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47–64 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Cross-presentation is important for both induction of immune responses by dying cells and tolerance induction.

    “As discussed in the next section, such cross-presentation is important not only for the induction of immune responses by dying cells, but also for tolerance induction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Dying cells can promote an effective immune response, but under different conditions can produce immune tolerance.

    “While dying cells can promote an effective immune response, we know that under different conditions such cells can produce immune tolerance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitotic catastrophe leads to cell death during or after mitosis and is discernible by multi- or micronucleation and/or mitotic arrest.

    “Mitotic catastrophe leads to cell death during or after mitosis and is morphologically discernible by multi- or micronucleation and/or mitotic arrest before the cells adopts an apoptotic or necrotic aspects 113.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Golstein, P. & Kroemer, G. Cell death by necrosis: towards a molecular definition. Trends Biochem. Sci. 32, 37–43 (2007). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Necrosis has traditionally been considered an accidental, uncontrolled form of cell death occurring only in pathological circumstances.

    “Necrosis has traditionally been considered merely as an accidental, uncontrolled form of cell death that only occurs in pathological circumstances.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 15 Feb 2009 (doi:10.1038/nature07750). This paper reports the identification of a new PRR on DCs that senses the presence of an unknown intracellular ligand that becomes accessible in dead cells following permeabilization of the plasma membrane and directs antigens for cross-presentation. source

      Not checked in the free run.

    • cites [110] Beutler, B. & Moresco, E. M. The forward genetic dissection of afferent innate immunity. Curr. Top. Microbiol. Immunol. 321, 3–26 (2008).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Apoptosis is accompanied by cell rounding, pseudopod retraction, reduced cell volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), few or no ultrastructural changes in cytoplasmic organelles, and plasma membrane blebbing, with cell integrity maintained until the final stages.

    “Apoptosis is accompanied by rounding-up of the cell, retraction of pseudopods, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), few or no ultrastructural modifications of cytoplasmic organelles, and plasma membrane blebbing but cell integrity is maintained until the final stages of the process.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 15 Feb 2009 (doi:10.1038/nature07750). This paper reports the identification of a new PRR on DCs that senses the presence of an unknown intracellular ligand that becomes accessible in dead cells following permeabilization of the plasma membrane and directs antigens for cross-presentation. source

      Not checked in the free run.

    • cites [110] Beutler, B. & Moresco, E. M. The forward genetic dissection of afferent innate immunity. Curr. Top. Microbiol. Immunol. 321, 3–26 (2008).

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The caspase-dependent mechanisms responsible for phospholipid scrambling have been elusive.

    “To date, the caspase-dependent mechanisms responsible for phospholipid scrambling have been elusive.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Miyanishi, M. et al. Identification of Tim4 as a phosphatidylserine receptor. Nature 450, 435–439 (2007). source

      Not checked in the free run.

    • cites [114] Vakifahmetoglu, H., Olsson, M. & Zhivotovsky, B. Death through a tragedy: mitotic catastrophe. Cell Death Differ. 15, 1153–1162 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caspases cleave and activate phospholipase A2, although this is not required for production of the lipid signal.

    “Caspases cleave and thereby activate PLA2, although this is not required for production of the lipid signal.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Panaretakis, T. et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ. 15, 1499–1509 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pyroptosis involves caspase-1 activating complexes known as inflammasomes.

    “Pyroptosis involves the crucial contribution of a particular set of caspase-1 activating complexes, known as the inflammasomes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [107] Jeannin, P., Jaillon, S. & Delneste, Y. Pattern recognition receptors in the immune response against dying cells. Curr. Opin. Immunol. 20, 530–537 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Polynucleotides and oligonucleotides from degrading DNA or RNA can act on TLR3, TLR7, TLR8, or TLR9 and on intracellular receptors RIG1, MDA5, or LGP2, while ATP and its degradation products may activate or inhibit distinct classes of purinergic receptors.

    “Polynucleotides and oligonucleotides derived from degrading DNA or RNA can act on TLR3, TLR7, TLR8, or TLR9 as well as on intracellular receptors including RIG1, MDA5, or LGP2, while ATP and its degradation products may activate or inhibit distinct classes of purinergic receptors 45,108,109.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [45] Hanley, P. J. et al. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages. Proc. Natl Acad. Sci. USA 101, 9479–9484 (2004). source

      Not checked in the free run.

    • cites [108] Ting, J. P., Willingham, S. B. & Bergstralh, D. T. NLRs at the intersection of cell death and immunity. Nature Rev. Immunol. 8, 372–379 (2008). source

      Not checked in the free run.

    • cites [109] Di Virgilio, F. Liaisons dangereuses: P2X(7) and the inflammasome. Trends Pharmacol. Sci. 28, 465–472 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD31 and CD47 are examples of don't-eat-me signals, although how cell death negates them remains unexplored.

    “Examples of such signals are CD31 117 and CD47 118, although how these molecules are negated by cell death remains unexplored.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [117] Miksa, M., Amin, D., Wu, R., Ravikumar, T. S. & Wang, P. Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. Mol. Med. 13, 553–560 (2007). source

      Not checked in the free run.

    • cites [118] Brown, S. et al. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203 (2002). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Necrosis is morphologically characterized by cell volume gain (oncosis), organelle swelling, plasma membrane rupture, and loss of intracellular contents.

    “Necrosis is morphologically characterized by a gain in cell volume (oncosis), swelling of organelles, plasma membrane rupture and subsequent loss of intracellular contents.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 15 Feb 2009 (doi:10.1038/nature07750). This paper reports the identification of a new PRR on DCs that senses the presence of an unknown intracellular ligand that becomes accessible in dead cells following permeabilization of the plasma membrane and directs antigens for cross-presentation. source

      Not checked in the free run.

    • cites [110] Beutler, B. & Moresco, E. M. The forward genetic dissection of afferent innate immunity. Curr. Top. Microbiol. Immunol. 321, 3–26 (2008).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagic cell death occurs without chromatin condensation but with massive autophagic vacuolization of the cytoplasm.

    “Autophagic cell death occurs in the absence of chromatin condensation but is accompanied by massive autophagic vacuolization of the cytoplasm.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 15 Feb 2009 (doi:10.1038/nature07750). This paper reports the identification of a new PRR on DCs that senses the presence of an unknown intracellular ligand that becomes accessible in dead cells following permeabilization of the plasma membrane and directs antigens for cross-presentation. source

      Not checked in the free run.

    • cites [110] Beutler, B. & Moresco, E. M. The forward genetic dissection of afferent innate immunity. Curr. Top. Microbiol. Immunol. 321, 3–26 (2008).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HMGB1 may act on RAGE and possibly on TLR2 and TLR4, although the TLR action is controversial.

    “Thus, HMGB1 may act on the receptor for advanced glycated endproducts (RAGEs) and possibly the toll-like receptors (TLRs) including TLR2 and TLR4 51,52, although the latter are controversial 53.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [51] Kazama, H. et al. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity 29, 21–32 (2008). This study 'connects the dots' from caspase activation to ROS production to modification of HMGB1 and to immune tolerance. source

      Not checked in the free run.

    • cites [52] Bianchi, M. E. & Manfredi, A. A. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol. Rev. 220, 35–46 (2007). source

      Not checked in the free run.

    • cites [53] Marshak-Rothstein, A. Toll-like receptors in systemic autoimmune disease. Nature Rev. Immunol. 6, 823–835 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fractalkine CX3CL1 recruits phagocytes and induces MFG-E8, a bridging molecule for detection of apoptotic cells.

    “Another such signal is the fractalkine CX3CL1, which recruits phagocytes 115 and induces one of the bridging molecules for detection of apoptotic cells, MFG-E8 116.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [115] Erwig, L. P. & Henson, P. M. Clearance of apoptotic cells by phagocytes. Cell Death Differ. 15, 243–250 (2008). source

      Not checked in the free run.

    • cites [116] Truman, L. A. et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 5026–5036 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The term 'autophagic cell death' is a misnomer, because it simply describes cell death that occurs alongside autophagy.

    “In this sense, the term “autophagic cell death” is a misnomer 61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Obeid, M. et al. Calreticulin exposure is required for the immunogenicity of γ-irradiation and UVC light-induced apoptosis. Cell Death Differ. 14, 1848–1850 (2007). source

      Not checked in the free run.

43 of 43

  • The paper relies on this without support.

    Normal tissue turnover in humans does not usually cause autoreactivity.

    “In most cases, this does not cause autoreactivity.”

  • The paper relies on this without support.

    Dead cells are either shed from bodily surfaces or cleared by engulfment.

    “Dead cells are either shed from bodily surfaces (such as the skin or mucosa) or they are cleared via engulfment by other cells.”

  • The paper relies on this without support.

    DC can direct immune responses by presenting antigens from dying cells to T cells.

    “DC can direct the immune response by presenting antigens that are associated with dying cells to T cells.”

  • The paper relies on this without support.

    Failure or delay in removing dying cells can have autoimmune consequences.

    “We know that a failure or delay of removing dying cells can have autoimmune consequences”

  • The paper relies on this without support.

    The mechanisms for removal of corpses are highly conserved in animals that lack adaptive immune systems, and such animals show no inflammatory response to dead cells that are not removed.

    “the mechanisms for removal of corpses is highly conserved in animals that have no adaptive immune systems and do not show anything resembling inflammatory responses to the presence of dead cells that are not removed”
5 of 5

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Authors
Green, D. R., Ferguson, T., Zitvogel, L., & Kroemer, G.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Washington University in St. Louis (US)
  • Inserm (FR)
Corresponding author
  • Green, Douglas R.
  • Kroemer, Guido
ORCID
Venue
Nature Reviews Immunology
Publisher
Springer Science and Business Media LLC
Published
2009-05
Volume
9
Issue
5
Pages
353-363
ISSN
  • 1474-1733 (ISSN-L)
  • 1474-1741
DOI
10.1038/nri2545
PMC
PMC2818721
OpenAlex
W2123469465
Semantic Scholar
b09000d1ccd5bbeac761e643f098d499ac5733fa
Cited by
1,176
References
126
Citations by year
2026: 41 · 2025: 49 · 2024: 61 · 2023: 89 · 2022: 75 · 2021: 97 · 2020: 87 · 2019: 60 · 2018: 62 · 2017: 61 · 2016: 56 · 2015: 66 · 2014: 57 · 2013: 89 · 2012: 75
FWCI
5.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Fondation pour la Recherche Médicale
  • Ligue Contre le Cancer
  • Institut National Du Cancer
  • National Eye Institute (EY 02687, P30EY002687, EY15570, F32EY006765, EY06765, R01EY015570, R01EY006765)
  • National Cancer Institute (P01CA069381)
  • National Institute of General Medical Sciences (R37GM052735)
  • National Institute of Allergy and Infectious Diseases (R01AI044828, R01AI040646, R01AI047891)
  • Institute of Cancer Research
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
immunogenic cell death, cell death, immune tolerance, autoimmunity, tumor immunology, anticancer agents, pathogen clearance, tissue turnover
MeSH terms
Animals, Humans, Immune Tolerance, Signal Transduction, Cell Death, Caspases, Immunogenetic Phenomena

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

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