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PMID: 19365408 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

Immunogenic and tolerogenic cell death.

Nature reviews. Immunology ·Vol. 9 ·No. 5 ·2009-05-00 ·Pages 353-63

Green DR, Ferguson T, Zitvogel L, Kroemer G

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'.

MeSH Terms
Animals Caspases/metabolism Cell Death/immunology Humans Immune Tolerance/immunology Immunogenetic Phenomena/immunology Signal Transduction/immunology
Chemicals
Caspases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Green Douglas R
Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. e-mails: [email protected]
Ferguson Thomas
Zitvogel Laurence
Kroemer Guido
References (121)
121 references, click to expand
  1. Calreticulin exposure dictates the immunogenicity of cancer cell death.
    Nat Med. 2007 Jan;13(1):54-61 PMID: 17187072
  2. NALP inflammasomes: a central role in innate immunity.
    Semin Immunopathol. 2007 Sep;29(3):213-29 PMID: 17703304
  3. Liaisons dangereuses: P2X(7) and the inflammasome.
    Trends Pharmacol Sci. 2007 Sep;28(9):465-72 PMID: 17692395
  4. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network.
    Cell. 2008 Jun 13;133(6):1019-31 PMID: 18555778
  5. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis.
    Blood. 2008 Dec 15;112(13):5026-36 PMID: 18799722
  6. Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages.
    Mol Med. 2007 Nov-Dec;13(11-12):553-60 PMID: 17673941
  7. Identification of a factor that links apoptotic cells to phagocytes.
    Nature. 2002 May 9;417(6885):182-7 PMID: 12000961
  8. Immunological aspects of cancer chemotherapy.
    Nat Rev Immunol. 2008 Jan;8(1):59-73 PMID: 18097448
  9. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes.
    Nat Cell Biol. 2004 Dec;6(12):1221-8 PMID: 15558033
  10. Clearance deficiency and systemic lupus erythematosus (SLE).
    J Autoimmun. 2007 Mar-May;28(2-3):114-21 PMID: 17368845
  11. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice.
    Science. 2004 May 21;304(5674):1147-50 PMID: 15155946
  12. Intravenous infusion of syngeneic apoptotic cells by photopheresis induces antigen-specific regulatory T cells.
    J Immunol. 2005 May 15;174(10):5968-76 PMID: 15879089
  13. Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit of complex I of the electron transport chain.
    Cell. 2004 Jun 11;117(6):773-86 PMID: 15186778
  14. Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.
    Cell Death Differ. 2006 Jan;13(1):41-52 PMID: 15962005
  15. Role of antigen-presenting cells in mediating tolerance and autoimmunity.
    J Exp Med. 2000 Jun 5;191(11):2021-7 PMID: 10839816
  16. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
    J Clin Invest. 1998 Feb 15;101(4):890-8 PMID: 9466984
  17. Tolerogenic dendritic cells.
    Annu Rev Immunol. 2003;21:685-711 PMID: 12615891
  18. Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens.
    J Clin Invest. 2007 Aug;117(8):2268-78 PMID: 17657313
  19. The relationship between apoptosis and high-mobility group protein 1 release from murine macrophages stimulated with lipopolysaccharide or polyinosinic-polycytidylic acid.
    J Immunol. 2007 May 15;178(10):6495-503 PMID: 17475879
  20. Gout-associated uric acid crystals activate the NALP3 inflammasome.
    Nature. 2006 Mar 9;440(7081):237-41 PMID: 16407889
  21. Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis.
    J Exp Med. 1998 Sep 7;188(5):887-96 PMID: 9730890
  22. Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells.
    Nat Immunol. 2001 Nov;2(11):1010-7 PMID: 11590405
  23. Differential antigen processing by dendritic cell subsets in vivo.
    Science. 2007 Jan 5;315(5808):107-11 PMID: 17204652
  24. Annexin I is an endogenous ligand that mediates apoptotic cell engulfment.
    Dev Cell. 2003 Apr;4(4):587-98 PMID: 12689596
  25. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.
    Immunity. 2008 Jul 18;29(1):21-32 PMID: 18631454
  26. Bortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications.
    Blood. 2007 Jun 1;109(11):4839-45 PMID: 17299090
  27. A critical role for the proapoptotic protein bid in ultraviolet-induced immune suppression and cutaneous apoptosis.
    J Immunol. 2008 Sep 1;181(5):3077-88 PMID: 18713978
  28. Molecular identification of a danger signal that alerts the immune system to dying cells.
    Nature. 2003 Oct 2;425(6957):516-21 PMID: 14520412
  29. Mice lacking the orphan G protein-coupled receptor G2A develop a late-onset autoimmune syndrome.
    Immunity. 2001 May;14(5):561-71 PMID: 11371358
  30. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal.
    Cell. 2003 Jun 13;113(6):717-30 PMID: 12809603
  31. Dual immunological unresponsiveness induced by cell membrane coupled hapten or antigen.
    Nature. 1966 Oct 8;212(5058):156-7 PMID: 5972208
  32. NLRs at the intersection of cell death and immunity.
    Nat Rev Immunol. 2008 May;8(5):372-9 PMID: 18362948
  33. Toll-like receptors in systemic autoimmune disease.
    Nat Rev Immunol. 2006 Nov;6(11):823-35 PMID: 17063184
  34. Apoptosis-dependent subversion of the T-lymphocyte epitope hierarchy in lymphoma cells.
    Cancer Res. 2002 Feb 15;62(4):1116-22 PMID: 11861391
  35. The CD8alpha(+) dendritic cell is responsible for inducing peripheral self-tolerance to tissue-associated antigens.
    J Exp Med. 2002 Oct 21;196(8):1099-104 PMID: 12391021
  36. Cross-tolerance: a pathway for inducing tolerance to peripheral tissue antigens.
    J Exp Med. 1998 May 18;187(10):1549-53 PMID: 9584133
  37. The danger model: a renewed sense of self.
    Science. 2002 Apr 12;296(5566):301-5 PMID: 11951032
  38. Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and cross-priming of CD8(+) T cells produce active immune unresponsiveness.
    J Immunol. 2002 Jun 1;168(11):5589-95 PMID: 12023355
  39. Necrosis, a well-orchestrated form of cell demise: signalling cascades, important mediators and concomitant immune response.
    Biochim Biophys Acta. 2006 Sep-Oct;1757(9-10):1371-87 PMID: 16950166
  40. CD8(+) but not CD8(-) dendritic cells cross-prime cytotoxic T cells in vivo.
    J Exp Med. 2000 Dec 18;192(12):1685-96 PMID: 11120766
  41. Autophagic cell death: the story of a misnomer.
    Nat Rev Mol Cell Biol. 2008 Dec;9(12):1004-10 PMID: 18971948
  42. Studies on hapten specific T cell immunity and suppression.
    Immunol Rev. 1980;50:163-86 PMID: 6991390
  43. Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection.
    Nat Med. 2007 Dec;13(12):1431-9 PMID: 18026114
  44. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes.
    J Exp Med. 1998 Oct 5;188(7):1359-68 PMID: 9763615
  45. The antiapoptotic activity of insect IAPs requires activation by an evolutionarily conserved mechanism.
    Cell Death Differ. 2007 Jun;14(6):1191-201 PMID: 17347664
  46. Resolution of inflammation: the beginning programs the end.
    Nat Immunol. 2005 Dec;6(12):1191-7 PMID: 16369558
  47. The induction of tolerance by dendritic cells that have captured apoptotic cells.
    J Exp Med. 2000 Feb 7;191(3):411-6 PMID: 10662786
  48. CD95-induced apoptosis of lymphocytes in an immune privileged site induces immunological tolerance.
    Immunity. 1996 Jul;5(1):7-16 PMID: 8758890
  49. Peripheral deletion of antigen-specific T cells leads to long-term tolerance mediated by CD8+ cytotoxic cells.
    J Immunol. 2005 Apr 1;174(7):4098-104 PMID: 15778368
  50. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment.
    Nature. 2002 Jul 11;418(6894):200-3 PMID: 12110892
  51. Autophosphorylation docking site Tyr-867 in Mer receptor tyrosine kinase allows for dissociation of multiple signaling pathways for phagocytosis of apoptotic cells and down-modulation of lipopolysaccharide-inducible NF-kappaB transcriptional activation.
    J Biol Chem. 2008 Feb 8;283(6):3618-3627 PMID: 18039660
  52. Triggering of dendritic cell responses after exposure to activated, but not resting, apoptotic PBMCs.
    J Immunol. 2007 Aug 1;179(3):1711-20 PMID: 17641037
  53. Interleukin-10 expression in macrophages during phagocytosis of apoptotic cells is mediated by homeodomain proteins Pbx1 and Prep-1.
    Immunity. 2007 Dec;27(6):952-64 PMID: 18093541
  54. Ecto-calreticulin in immunogenic chemotherapy.
    Immunol Rev. 2007 Dec;220:22-34 PMID: 17979837
  55. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor.
    Nature. 2005 Aug 25;436(7054):1186-90 PMID: 15995699
  56. TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu.
    Immunity. 2001 Jun;14(6):715-25 PMID: 11420042
  57. Chemokine signaling via the CXCR2 receptor reinforces senescence.
    Cell. 2008 Jun 13;133(6):1006-18 PMID: 18555777
  58. Epitope landscape in breast and colorectal cancer.
    Cancer Res. 2008 Feb 1;68(3):889-92 PMID: 18245491
  59. Migration to apoptotic "find-me" signals is mediated via the phagocyte receptor G2A.
    J Biol Chem. 2008 Feb 29;283(9):5296-305 PMID: 18089568
  60. Cellular and molecular mechanisms of liver tolerance.
    Immunol Rev. 2006 Oct;213:101-18 PMID: 16972899
  61. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages.
    Nature. 2000 Jan 13;403(6766):199-203 PMID: 10646605
  62. Apoptotic cells induce tolerance by generating helpless CD8+ T cells that produce TRAIL.
    J Immunol. 2007 Mar 1;178(5):2679-87 PMID: 17312109
  63. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl.
    J Exp Med. 1995 Nov 1;182(5):1545-56 PMID: 7595224
  64. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy.
    Nat Med. 2007 Sep;13(9):1050-9 PMID: 17704786
  65. Immunogenic chemotherapy: discovery of a critical protein through proteomic analyses of tumor cells.
    Cancer Genomics Proteomics. 2007 Mar-Apr;4(2):65-70 PMID: 17804868
  66. Mincle is an ITAM-coupled activating receptor that senses damaged cells.
    Nat Immunol. 2008 Oct;9(10):1179-88 PMID: 18776906
  67. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity.
    Nature. 2009 Apr 16;458(7240):899-903 PMID: 19219027
  68. Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus.
    J Leukoc Biol. 2008 May;83(5):1300-7 PMID: 18303131
  69. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE.
    Nat Immunol. 2007 May;8(5):487-96 PMID: 17417641
  70. Decoding the patterns of self and nonself by the innate immune system.
    Science. 2002 Apr 12;296(5566):298-300 PMID: 11951031
  71. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis.
    Nature. 2007 Apr 26;446(7139):1091-5 PMID: 17410128
  72. Molecular determinants of immunogenic cell death: surface exposure of calreticulin makes the difference.
    J Mol Med (Berl). 2007 Oct;85(10):1069-76 PMID: 17891368
  73. Defective CD8 T cell memory following acute infection without CD4 T cell help.
    Science. 2003 Apr 11;300(5617):339-42 PMID: 12690202
  74. Identification of Tim4 as a phosphatidylserine receptor.
    Nature. 2007 Nov 15;450(7168):435-9 PMID: 17960135
  75. The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo.
    Immunity. 1994 Dec;1(9):741-9 PMID: 7895163
  76. Apoptosis in the pathogenesis and treatment of disease.
    Science. 1995 Mar 10;267(5203):1456-62 PMID: 7878464
  77. Inefficient clearance of dying cells and autoreactivity.
    Curr Top Microbiol Immunol. 2006;305:161-76 PMID: 16724805
  78. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation.
    J Clin Invest. 2002 Jan;109(1):41-50 PMID: 11781349
  79. Pretransplantation blood transfusion revisited.
    N Engl J Med. 1991 Oct 24;325(17):1210-3 PMID: 1922208
  80. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death.
    J Exp Med. 2005 Dec 19;202(12):1691-701 PMID: 16365148
  81. Immune response against dying tumor cells.
    Adv Immunol. 2004;84:131-79 PMID: 15246252
  82. The immune response and the eye. III. Anterior chamber-associated immune deviation can be adoptively transferred by serum.
    J Immunol. 1989 Aug 1;143(3):821-6 PMID: 2473113
  83. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death.
    Cell Death Differ. 2008 Sep;15(9):1499-509 PMID: 18464797
  84. Engulfment of apoptotic cells: signals for a good meal.
    Nat Rev Immunol. 2007 Dec;7(12):964-74 PMID: 18037898
  85. Death through a tragedy: mitotic catastrophe.
    Cell Death Differ. 2008 Jul;15(7):1153-62 PMID: 18404154
  86. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7.
    Cell. 2008 Feb 8;132(3):363-74 PMID: 18267069
  87. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte.
    Cell. 2005 Oct 21;123(2):321-34 PMID: 16239148
  88. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells.
    J Exp Med. 2000 Feb 7;191(3):423-34 PMID: 10662788
  89. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.
    Br J Cancer. 1972 Aug;26(4):239-57 PMID: 4561027
  90. The induction of tolerance to DNFB contact sensitivity by using hapten-modified lymphoid cells. III. Effects of hapten concentration on the ability of MLS-disparate cells to induce rapid unresponsiveness.
    J Immunol. 1980 Aug;125(2):807-13 PMID: 6156215
  91. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death.
    Nature. 2005 Mar 3;434(7029):88-93 PMID: 15744305
  92. Cell death by necrosis: towards a molecular definition.
    Trends Biochem Sci. 2007 Jan;32(1):37-43 PMID: 17141506
  93. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes.
    Nature. 2003 Feb 20;421(6925):852-6 PMID: 12594515
  94. Immunosuppressive effects of apoptotic cells.
    Nature. 1997 Nov 27;390(6658):350-1 PMID: 9389474
  95. Extracellular ATP induces oscillations of intracellular Ca2+ and membrane potential and promotes transcription of IL-6 in macrophages.
    Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9479-84 PMID: 15194822
  96. Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient.
    Cell Death Differ. 2004 Dec;11(12):1258-64 PMID: 15375386
  97. Requirements for apoptotic cell contact in regulation of macrophage responses.
    J Immunol. 2006 Sep 15;177(6):4047-54 PMID: 16951368
  98. Ultraviolet light-induced immune tolerance is mediated via the Fas/Fas-ligand system.
    J Immunol. 1998 May 1;160(9):4262-70 PMID: 9574528
  99. The extracellular release of HMGB1 during apoptotic cell death.
    Am J Physiol Cell Physiol. 2006 Dec;291(6):C1318-25 PMID: 16855214
  100. Epidermal viral immunity induced by CD8alpha+ dendritic cells but not by Langerhans cells.
    Science. 2003 Sep 26;301(5641):1925-8 PMID: 14512632
  101. Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation.
    Nature. 2009 Mar 5;458(7234):78-82 PMID: 19262671
  102. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.
    Nature. 2002 Jul 11;418(6894):191-5 PMID: 12110890
  103. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity.
    Immunol Rev. 2007 Dec;220:35-46 PMID: 17979838
  104. Pattern recognition receptors in the immune response against dying cells.
    Curr Opin Immunol. 2008 Oct;20(5):530-7 PMID: 18555676
  105. Changing story of the receptor for phosphatidylserine-dependent clearance of apoptotic cells.
    EMBO Rep. 2007 May;8(5):465-9 PMID: 17471263
  106. Metabolic catastrophe as a means to cancer cell death.
    J Cell Sci. 2007 Feb 1;120(Pt 3):379-83 PMID: 17251378
  107. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.
    Nature. 2007 Feb 8;445(7128):656-60 PMID: 17251933
  108. Studies on transplantation immunity. IV. Murine natural immunity to lymphoid cells in vivo.
    Eur J Immunol. 1980 Apr;10(4):250-7 PMID: 7398757
  109. The forward genetic dissection of afferent innate immunity.
    Curr Top Microbiol Immunol. 2008;321:3-26 PMID: 18727485
  110. Cell death modalities: classification and pathophysiological implications.
    Cell Death Differ. 2007 Jul;14(7):1237-43 PMID: 17431418
  111. The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo.
    J Exp Med. 2002 May 20;195(10):1289-302 PMID: 12021309
  112. Autophagy regulates selective HMGB1 release in tumor cells that are destined to die.
    Cell Death Differ. 2009 Jan;16(1):175-83 PMID: 18846108
  113. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions.
    Nature. 1998 Jun 4;393(6684):480-3 PMID: 9624005
  114. Regulation of the hapten-specific T cell response. I. Preferential induction of hyporesponsiveness to the D-end of the major histocompatibility complex in the hapten-specific cytotoxic T cell response.
    J Immunol. 1983 Nov;131(5):2184-9 PMID: 6195256
  115. Clearance of apoptotic cells by phagocytes.
    Cell Death Differ. 2008 Feb;15(2):243-50 PMID: 17571081
  116. Therapeutic cancer vaccines.
    Curr Opin Immunol. 2006 Apr;18(2):201-5 PMID: 16464565
  117. The acquired immune system: a vantage from beneath.
    Immunity. 2004 Nov;21(5):607-15 PMID: 15539148
  118. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis.
    Cell Death Differ. 2007 Oct;14(10):1848-50 PMID: 17657249
  119. Interaction between phosphatidylserine and the phosphatidylserine receptor inhibits immune responses in vivo.
    J Immunol. 2005 Feb 1;174(3):1393-404 PMID: 15661897
  120. Cross-presentation, dendritic cells, tolerance and immunity.
    Annu Rev Immunol. 2001;19:47-64 PMID: 11244030
  121. Autophagy gene-dependent clearance of apoptotic cells during embryonic development.
    Cell. 2007 Mar 9;128(5):931-46 PMID: 17350577
Article Info
Journal
Nature reviews. Immunology
Abbr.
Nat Rev Immunol
ISSN
1474-1741
DOI
10.1038/nri2545
Email
[email protected]
Published
2009-05-00
Pages
353-63
Language
English
Region
England
NLM ID
101124169
PMCID
PMC2818721
Subset
IM
Grants
NEI NIH HHS · F32 EY006765 · United States
NIAID NIH HHS · R01 AI047891 · United States
NEI NIH HHS · R01 EY006765 · United States
NEI NIH HHS · EY06765 · United States
NEI NIH HHS · EY15570 · United States
NCI NIH HHS · P01 CA069381-140010 · United States
NIAID NIH HHS · R01 AI044828 · United States
NIAID NIH HHS · R01 AI040646-14 · United States
NIAID NIH HHS · R01 AI047891-11 · United States
NEI NIH HHS · P30 EY002687 · United States
NEI NIH HHS · R01 EY015570 · United States
NIGMS NIH HHS · R37 GM052735-19 · United States
NIGMS NIH HHS · R37 GM052735 · United States
NEI NIH HHS · EY02687 · United States
NIAID NIH HHS · R01 AI044828-12 · United States
NCI NIH HHS · P01 CA069381 · United States
NIAID NIH HHS · R01 AI040646 · United States
External Links
PubMed source DOI: 10.1038/nri2545 PMC Full Text View journal details
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