Dendritic cells (DCs) can take up dying cells and cross-present antigens derived from the dying cells to antigen-specific CD8+ T cells. Efficient T cell cross-priming is dependent on a set of immunological signals provided by dying cells.
Dying cells expose and release 'find-me' and 'eat-me' signals to attract and stimulate phagocytosis. They also release immune-stimulatory molecules known as damage-associated molecular patterns (DAMPs), which can be sensed by phagocytes.
Cell death pathways are interconnected with innate immune pathways, resulting in simultaneous execution of cell death and activation of inflammatory pathways within dying cells.
Molecules that are generated de novo as a consequence of the programmed cell death and inflammatory pathways within dying cells are named inducible DAMPs (iDAMPs), in contrast to constitutive DAMPs (cDAMPs), which are present before the initiation of cell death. Hence, iDAMPs released by dying cells reflect the various stress pathways that are engaged during cell death.
iDAMPs may be the products of active RNA transcription and protein translation (for example, nuclear factor-κB-dependent inflammatory cytokines), or post-translational protein modifications (such as pro-interleukin-1β cleavage by caspase 1), or protein aggregates that propagate signalling upon phagocytosis (such as apoptosis-associated speck-like protein containing a CARD (ASC) specks).
In the cascade of immunological signals that leads to T cell priming, the activation of innate immune pathways within dying cells is an early immune signal that actively regulates the adaptive immune response.
Dying cells have an important role in the initiation of CD8+ T cell-mediated immunity. The cross-presentation of antigens derived from dying cells enables dendritic cells to present exogenous tissue-restricted or tumour-restricted proteins on MHC class I molecules. Importantly, this pathway has been implicated in multiple autoimmune diseases and accounts for the priming of tumour antigen-specific T cells. Recent data have revealed that in addition to antigen, dying cells provide inflammatory and immunogenic signals that determine the efficiency of CD8+ T cell cross-priming. The complexity of these signals has been evidenced by the multiple molecular pathways that result in cell death and that have now been shown to differentially influence antigen transfer and immunity. In this Review, we provide a detailed summary of both the passive and active signals that are generated by dying cells during their initiation of CD8+ T cell-mediated immunity. We propose that molecules generated alongside cell death pathways — inducible damage-associated molecular patterns (iDAMPs) — are upstream immunological cues that actively regulate adaptive immunity.
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Steinman, R. M. & Hemmi, H. Dendritic cells: translating innate to adaptive immunity. Curr. Top. Microbiol. Immunol. 311, 17–58 (2006).
Bevan, M. J. Cross-priming for a secondary cytotoxic response to minor H antigens with H-2 congenic cells which do not cross-react in the cytotoxic assay. J. Exp. Med. 143, 1283–1288 (1976).
Bevan, M. J. Minor H antigens introduced on H-2 different stimulating cells cross-react at the cytotoxic T cell level during in vivo priming. J. Immunol. 117, 2233–2238 (1976). In references 2 and 3, Michael Bevan is the first to suggest and experimentally demonstrate the ability to induce a cytotoxic T cell response specific to exogenous antigen, thereby introducing the biological process of cross-priming.
Suto, R. & Srivastava, P. K. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269, 1585–1588 (1995).
Basu, S. & Srivastava, P. K. Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumor- and peptide-specific immunity. J. Exp. Med. 189, 797–802 (1999). References 4 and 5 are the first to suggest that chaperone proteins such as HSPs and calreticulin have the ability to deliver antigens from an exogenous source into the cross-presentation pathway, and that this has implications for tumour immunity.
Srivastava, P. K. Immunotherapy of human cancer: lessons from mice. Nat. Immunol. 1, 363–366 (2000).
Albert, M. L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86–89 (1998).
Albert, M. L. et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat. Med. 4, 1321–1324 (1998). References 7 and 8 establish that dying cells are a source of viral or tumour antigens for cross-priming.
Albert, M. L. et al. Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes. J. Exp. Med. 188, 1359–1368 (1998).
Regnault, A. et al. Fcγ receptor-mediated induction of dendritic cell maturation and major histocompatibility complex class I-restricted antigen presentation after immune complex internalization. J. Exp. Med. 189, 371–380 (1999).
Rodriguez, A., Regnault, A., Kleijmeer, M., Ricciardi-Castagnoli, P. & Amigorena, S. Selective transport of internalized antigens to the cytosol for MHC class I presentation in dendritic cells. Nat. Cell Biol. 1, 362–368 (1999).
Bender, A., Bui, L. K., Feldman, M. A., Larsson, M. & Bhardwaj, N. Inactivated influenza virus, when presented on dendritic cells, elicits human CD8+ cytolytic T cell responses. J. Exp. Med. 182, 1663–1671 (1995).
Buseyne, F. et al. MHC-I-restricted presentation of HIV-1 virion antigens without viral replication. Nat. Med. 7, 344–349 (2001).
Kurts, C., Robinson, B. W. S. & Knolle, P. A. Cross-priming in health and disease. Nat. Rev. Immunol. 10, 403–414 (2010).
Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).
Heath, W. R. & Carbone, F. R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47–64 (2001).
Medzhitov, R. & Janeway, C. A. Decoding the patterns of self and nonself by the innate immune system. Science 296, 298–300 (2002).
Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).
Tang, D., Kang, R., Coyne, C. B., Zeh, H. J. & Lotze, M. T. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249, 158–175 (2012).
Albert, M. L., Jegathesan, M. & Darnell, R. B. Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells. Nat. Immunol. 2, 1010–1017 (2001).
Curtsinger, J. M., Lins, D. C. & Mescher, M. F. Signal 3 determines tolerance versus full activation of naive CD8 T cells: dissociating proliferation and development of effector function. J. Exp. Med. 197, 1141–1151 (2003). This study demonstrates the requirement for a third signal, named 'signal 3', for the induction of effector function in engaged CD8+ T cells. These signals are identified as inflammatory cytokines released by DCs.
Curtsinger, J. M. & Mescher, M. F. Inflammatory cytokines as a third signal for T cell activation. Curr. Opin. Immunol. 22, 333–340 (2010).
Metchnikoff, E. Essais Optimistes (Maloine, 1907).
Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).
Ellis, H. M. & Horvitz, H. R. Genetic control of programmed cell death in the nematode C. elegans. Cell 44, 817–829 (1986).
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).
Ferguson, T. A. et al. Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and cross-priming of CD8+ T cells produce active immune unresponsiveness. J. Immunol. 168, 5589–5595 (2002).
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).
Sun, E. et al. Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient. Cell Death Differ. 11, 1258–1264 (2004).
Shi, Y., Evans, J. E. & Rock, K. L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).
Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nat. Med. 5, 1249–1255 (1999).
Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002). References 30–32 are the first to recognize and identify endogenous molecules that are released by necrotic cells and that trigger immune responses. Reference 30 demonstrates that uric acid can induce CD8+ T cell-mediated immunity.
Martin, S. J., Henry, C. M. & Cullen, S. P. A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol. Cell 46, 387–397 (2012).
Turley, S., Poirot, L., Hattori, M., Benoist, C. & Mathis, D. Physiological β cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J. Exp. Med. 198, 1527–1537 (2003).
Rawson, P. M. et al. Cross-presentation of caspase-cleaved apoptotic self antigens in HIV infection. Nat. Med. 13, 1431–1439 (2007).
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).
Green, D. R., Ferguson, T., Zitvogel, L. & Kroemer, G. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9, 353–363 (2009).
Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).
Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005). This paper is the first to formally show that chemotherapy may induce immunogenic apoptosis. Intriguingly, caspase activation is shown to be required for the immunogenicity of doxorubicin-induced apoptosis.
Tesniere, A. et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene 29, 482–491 (2010).
Zitvogel, L., Kepp, O. & Kroemer, G. Decoding cell death signals in inflammation and immunity. Cell 140, 798–804 (2010).
Ronchetti, A. et al. Immunogenicity of apoptotic cells in vivo: role of antigen load, antigen-presenting cells, and cytokines. J. Immunol. 163, 130–136 (1999).
Scheffer, S. R. et al. Apoptotic, but not necrotic, tumor cell vaccines induce a potent immune response in vivo. Int. J. Cancer 103, 205–211 (2003).
Ochsenbein, A. F. et al. Immune surveillance against a solid tumor fails because of immunological ignorance. Proc. Natl Acad. Sci. USA 96, 2233–2238 (1999).
Gamrekelashvili, J. et al. Peptidases released by necrotic cells control CD8+ T cell cross-priming. J. Clin. Invest. 123, 4755–4768 (2013).
Blum, J. S., Wearsch, P. A. & Cresswell, P. Pathways of antigen processing. Annu. Rev. Immunol. 31, 443–473 (2013).
Nair-Gupta, P. & Blander, J. M. An updated view of the intracellular mechanisms regulating cross-presentation. Front. Immunol. 4, 401 (2013).
Ackerman, A. L., Giodini, A. & Cresswell, P. A role for the endoplasmic reticulum protein retrotranslocation machinery during crosspresentation by dendritic cells. Immunity 25, 607–617 (2006).
Guermonprez, P. et al. ER–phagosome fusion defines an MHC class I cross-presentation compartment in dendritic cells. Nature 425, 397–402 (2003).
Shen, L., Sigal, L. J., Boes, M. & Rock, K. L. Important role of cathepsin S in generating peptides for TAP-independent MHC class I crosspresentation in vivo. Immunity 21, 155–165 (2004).
Perot, B. P., Ingersoll, M. A. & Albert, M. L. The impact of macroautophagy on CD8+ T-cell-mediated antiviral immunity. Immunol. Rev. 255, 40–56 (2013).
Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965–975 (2002).
Kloetzel, P. M. Antigen processing by the proteasome. Nat. Rev. Mol. Cell Biol. 2, 179–187 (2001).
Blachère, N. E., Darnell, R. B. & Albert, M. L. Apoptotic cells deliver processed antigen to dendritic cells for cross-presentation. PLoS Biol. 3, e185 (2005).
McNulty, S. et al. Heat-shock proteins as dendritic cell-targeting vaccines — getting warmer. Immunology 139, 407–415 (2013).
Murshid, A., Gong, J. & Calderwood, S. K. The role of heat shock proteins in antigen cross presentation. Front. Immunol. 3, 63 (2012).
Yewdell, J. W. & Nicchitta, C. V. The DRiP hypothesis decennial: support, controversy, refinement and extension. Trends Immunol. 27, 368–373 (2006).
Antón, L. C. & Yewdell, J. W. Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors. J. Leukoc. Biol. 95, 551–562 (2014).
Jusforgues-Saklani, H. et al. Antigen persistence is required for dendritic cell licensing and CD8+ T cell cross-priming. J. Immunol. 181, 3067–3076 (2008).
Kurts, C., Miller, J. F., Subramaniam, R. M., Carbone, F. R. & Heath, W. R. Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J. Exp. Med. 188, 409–414 (1998).
Münz, C. Autophagy proteins in antigen processing for presentation on MHC molecules. Immunol. Rev. 272, 17–27 (2016).
Li, H., Li, Y., Jiao, J. & Hu, H.-M. Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response. Nat. Nanotechnol. 6, 645–650 (2011).
Johnstone, C. et al. Exogenous, TAP-independent lysosomal presentation of a respiratory syncytial virus CTL epitope. Immunol. Cell Biol. 90, 978–982 (2012).
Uhl, M. et al. Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells. Cell Death Differ. 16, 991–1005 (2009).
Accapezzato, D. et al. Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. J. Exp. Med. 202, 817–828 (2005).
Li, Y. et al. Efficient cross-presentation depends on autophagy in tumor cells. Cancer Res. 68, 6889–6895 (2008).
Li, Y. et al. Tumor-derived autophagosome vaccine: mechanism of cross-presentation and therapeutic efficacy. Clin. Cancer Res. 17, 7047–7057 (2011).
Elliott, M. R. & Ravichandran, K. S. The dynamics of apoptotic cell clearance. Dev. Cell 38, 147–160 (2016).
Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).
Chekeni, F. B. et al. Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis. Nature 467, 863–867 (2010). References 70 and 71 demonstrate that extracellular nucleotides such as ATP can function as 'find-me' signals released from dying cells by guiding the recruitment of myeloid cells. Furthermore, they elucidate a caspase-dependent mechanism for the release of such signals.
Cullen, S. P. et al. Fas/CD95-induced chemokines can serve as 'find-me' signals for apoptotic cells. Mol. Cell 49, 1034–1048 (2013). This paper demonstrates that apoptosis and RIPK1-dependent NF- κ B activation are simultaneously induced upon FAS stimulation, resulting in the production of inflammatory cytokines by apoptotic cells.
Brown, S. et al. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200–203 (2002).
Gardai, S. J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).
Fadok, V. A., Bratton, D. L. & Henson, P. M. Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J. Clin. Invest. 108, 957–962 (2001).
Kim, S., Elkon, K. B. & Ma, X. Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Immunity 21, 643–653 (2004).
Luo, B. et al. Erythropoeitin signaling in macrophages promotes dying cell clearance and immune tolerance. Immunity 44, 287–302 (2016).
Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).
Land, W. et al. The beneficial effect of human recombinant superoxide dismutase on acute and chronic rejection events in recipients of cadaveric renal transplants. Transplantation 57, 211–217 (1994). References 78 and 79 are the first to suggest and propose the danger theory. Reference 79 bases its conclusions on a clinical trial investigating the mechanisms of chronic rejection of renal transplants; reference 78 formulated the framework underlying the danger theory and established its theoretical framework.
Land, W. G. & Messmer, K. The danger theory in view of the injury hypothesis: 20 years later. Front. Immunol. 3, 349 (2012).
Yatim, N. et al. RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8+ T cells. Science 350, 328–334 (2015). This paper is the first to formally demonstrate that necroptosis efficiently induces the cross-priming of CD8+ T cells using the dimerizable system to induce specific cell death pathways. Importantly, this demonstrated that the release of endogenous DAMPs such as ATP and HMGB1 is insufficient, and that NF- κ B activation within dying cells is a key determinant for achieving T cell priming.
Zelenay, S. & Reis e Sousa, C. Adaptive immunity after cell death. Trends Immunol. 34, 329–335 (2013).
Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).
Harris, H. E., Andersson, U. & Pisetsky, D. S. HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat. Rev. Rheumatol. 8, 195–202 (2012).
Sancho, D. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009).
Zhang, J.-G. et al. The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity 36, 646–657 (2012).
Ahrens, S. et al. F-Actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36, 635–645 (2012).
Zelenay, S. et al. The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J. Clin. Invest. 122, 1615–1627 (2012). In papers 85–88, CLEC9A (also known as DNGR1) expressed on cross-presenting DCs is found to specifically recognize actin filaments released by necrotic cells. CLEC9A is also demonstrated to elicit antigen cross-presentation via diverting endosomes containing necrotic cargoes into the cross-presentation pathway.
Johansson, U., Walther-Jallow, L., Smed-Sörensen, A. & Spetz, A.-L. Triggering of dendritic cell responses after exposure to activated, but not resting, apoptotic PBMCs. J. Immunol. 179, 1711–1720 (2007).
Sistigu, A. et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301–1309 (2014). This paper demonstrates that immunogenic chemotherapy is dependent on the production of type I IFN by dying tumour cells and subsequent autocrine IFN receptor stimulation.
Aaes, T. L. et al. Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep. 15, 274–287 (2016).
Oberst, A. et al. Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activation. J. Biol. Chem. 285, 16632–16642 (2010).
Orozco, S. et al. RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ. 21, 1511–1521 (2014).
Weinlich, R. & Green, D. R. The two faces of receptor interacting protein kinase-1. Mol. Cell 56, 469–480 (2014).
Ofengeim, D. & Yuan, J. Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14, 727–736 (2013).
Newton, K. & Manning, G. Necroptosis and Inflammation. Annu. Rev. Biochem. 85, 743–763 (2016).
Dondelinger, Y., Hulpiau, P., Saeys, Y., Bertrand, M. J. M. & Vandenabeele, P. An evolutionary perspective on the necroptotic pathway. Trends Cell Biol. 26, 721–732 (2016).
Silke, J., Rickard, J. A. & Gerlic, M. The diverse role of RIP kinases in necroptosis and inflammation. Nat. Immunol. 16, 689–697 (2015).
Feoktistova, M. et al. cIAPs block ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell 43, 449–463 (2011).
Tenev, T. et al. The ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs. Mol. Cell 43, 432–448 (2011). References 99 and 100 are the first to describe a 2 MDa RIPK1-dependent cytosolic complex that assembles in response to genotoxic stress or polyinosinic–polycytidylic acid stimulation, and regulates cellular fates such as apoptosis and necroptosis. They also propose the term ripoptosome, which is now widely used and extended to other RIPK1-dependent cytosolic platforms.
Hsu, H., Huang, J., Shu, H. B., Baichwal, V. & Goeddel, D. V. TNF-dependent recruitment of the protein kinase RIP to the TNF receptor-1 signaling complex. Immunity 4, 387–396 (1996).
Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).
Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).
Rajput, A. et al. RIG-I RNA helicase activation of IRF3 transcription factor is negatively regulated by caspase-8-mediated cleavage of the RIP1 protein. Immunity 34, 340–351 (2011).
Michallet, M.-C. et al. TRADD protein is an essential component of the RIG-like helicase antiviral pathway. Immunity 28, 651–661 (2008).
Upton, J. W., Kaiser, W. J. & Mocarski, E. S. DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 11, 290–297 (2012).
Rebsamen, M. et al. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-κB. EMBO Rep. 10, 916–922 (2009).
Wang, X. et al. STING requires the adaptor TRIF to trigger innate immune responses to microbial infection. Cell Host Microbe 20, 329–341 (2016).
Tinel, A. & Tschopp, J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 304, 843–846 (2004). In papers 102–109, RIPK1 is found to regulate the assembly of cytosolic platforms in response to a diverse set of stimuli, hence coordinating the activation of innate immune and cell death pathways.
Janssens, S., Tinel, A., Lippens, S. & Tschopp, J. PIDD mediates NF-κB activation in response to DNA damage. Cell 123, 1079–1092 (2005).
Ando, K. et al. PIDD death-domain phosphorylation by ATM controls prodeath versus prosurvival PIDDosome signaling. Mol. Cell 47, 681–693 (2012).
Li, C. et al. Dendritic cells sequester antigenic epitopes for prolonged periods in the absence of antigen-encoding genetic information. Proc. Natl Acad. Sci. USA 109, 17543–17548 (2012).
Blachere, N. E. et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J. Exp. Med. 186, 1315–1322 (1997).
Sukkurwala, A. Q. et al. Immunogenic calreticulin exposure occurs through a phylogenetically conserved stress pathway involving the chemokine CXCL8. Cell Death Differ. 21, 59–68 (2014).
Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014).
White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549–1562 (2014). In references 113 and 114, the production of type I IFN during apoptosis is found to be actively suppressed by caspases, providing novel insights into the complex interactions between innate immune and cell death pathways.
Di Paolo, N. C., Doronin, K., Baldwin, L. K., Papayannopoulou, T. & Shayakhmetov, D. M. The transcription factor IRF3 triggers 'defensive suicide' necrosis in response to viral and bacterial pathogens. Cell Rep. 3, 1840–1846 (2013).
Blander, J. M. A long-awaited merger of the pathways mediating host defence and programmed cell death. Nat. Rev. Immunol. 14, 601–618 (2014). In this Review, Blander proposes a model for the intimate connection between pathways regulating cell death and innate immunity, and highlights the multiple nodal proteins that may simultaneously induce both cell death and inflammatory pathways.
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Martin, S. J. Cell death and inflammation: the case for IL-1 family cytokines as the canonical DAMPs of the immune system. FEBS J. 283, 2599–2615 (2016). This review proposes that IL-1 family members released by dying cells are the principal 'danger' molecules that signal the presence of dying cells to the immune system.
Martin, N. T. & Martin, M. U. Interleukin 33 is a guardian of barriers and a local alarmin. Nat. Immunol. 17, 122–131 (2016).
Peine, M., Marek, R. M. & Löhning, M. IL-33 in T cell differentiation, function, and immune homeostasis. Trends Immunol. 37, 321–333 (2016).
Pang, I. K., Ichinohe, T. & Iwasaki, A. IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8+ T cell responses to influenza A virus. Nat. Immunol. 14, 246–253 (2013). In this work, the authors demonstrate that DCs can be properly activated to stimulate antiviral CD8+ T cell-mediated immunity by IL-1R signalling, which suggests that IL-1 family members can substitute for PRR agonists.
Franklin, B. S. et al. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat. Immunol. 15, 727–737 (2014).
Baroja-Mazo, A. et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15, 738–748 (2014).
Li, J. et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339–350 (2012). This paper demonstrates that RIPK1 and RIPK3 can form functional amyloid structures that are required for necrosome assembly and downstream necroptosis induction. This work provides the first solid evidence that amyloid structures can be utilized for signal transduction in animal cells, and poses the question of their fate upon cell death and release.
Qing, D. Y. et al. Red blood cells induce necroptosis of lung endothelial cells and increase susceptibility to lung inflammation. Am. J. Respir. Crit. Care Med. 190, 1243–1254 (2014).
Lamkanfi, M. & Dixit, V. M. Mechanisms and functions of inflammasomes. Cell 157, 1013–1022 (2014).
Yatim, N. & Albert, M. L. Dying to replicate: the orchestration of the viral life cycle, cell death pathways, and immunity. Immunity 35, 478–490 (2011).
Ameisen, J. C. On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ. 9, 367–393 (2002).
Land, W. Allograft injury mediated by reactive oxygen species: from conserved proteins of Drosophila to acute and chronic rejection of human transplants. Part III: interaction of (oxidative) stress-induced heat shock proteins with Toll-like receptor-bearing cells of innate immunity and its consequences for the development of acute and chronic allograft rejection. Transplant. Rev. 17, 67–86 (2003).
Silverstein, A. M. & Rose, N. R. On the mystique of the immunological self. Immunol. Rev. 159, 197–206 (1997).
Kono, H. & Rock, K. L. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8, 279–289 (2008).
Oppenheim, J. J. & Yang, D. Alarmins: chemotactic activators of immune responses. Curr. Opin. Immunol. 17, 359–365 (2005).
Gerschenson, L. E. & Geske, F. J. Virchow and apoptosis. Am. J. Pathol. 158, 1543 (2001).
Kerr, J. F. A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J. Pathol. Bacteriol. 90, 419–435 (1965).
Kerr, J. F. Shrinkage necrosis: a distinct mode of cellular death. J. Pathol. 105, 13–20 (1971).
Horvitz, H. R. Nobel lecture. Worms, life and death. Biosci. Rep. 23, 239–303 (2003).
Yuan, J., Shaham, S., Ledoux, S., Ellis, H. M. & Horvitz, H. R. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 β-converting enzyme. Cell 75, 641–652 (1993).
Timmer, J. C. & Salvesen, G. S. Caspase substrates. Cell Death Differ. 14, 66–72 (2007).
Tait, S. W. G. & Green, D. R. Mitochondria and cell death: outer membrane permeabilization and beyond. Nat. Rev. Mol. Cell Biol. 11, 621–632 (2010).
Goldstein, J. C., Waterhouse, N. J., Juin, P., Evan, G. I. & Green, D. R. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat. Cell Biol. 2, 156–162 (2000).
Liu, X., Kim, C. N., Yang, J., Jemmerson, R. & Wang, X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell 86, 147–157 (1996).
Yuan, S. et al. Structure of an apoptosome–procaspase-9 CARD complex. Structure 18, 571–583 (2010).
Slee, E. A. et al. Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J. Cell Biol. 144, 281–292 (1999).
Wilson, N. S., Dixit, V. & Ashkenazi, A. Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat. Immunol. 10, 348–355 (2009).
Slee, E. A., Adrain, C. & Martin, S. J. Serial killers: ordering caspase activation events in apoptosis. Cell Death Differ. 6, 1067–1074 (1999).
Cerretti, D. P. et al. Molecular cloning of the interleukin-1 β converting enzyme. Science 256, 97–100 (1992).
Thornberry, N. A. et al. A novel heterodimeric cysteine protease is required for interleukin-1 β processing in monocytes. Nature 356, 768–774 (1992).
Kersse, K., Vanden Berghe, T., Lamkanfi, M. & Vandenabeele, P. A phylogenetic and functional overview of inflammatory caspases and caspase-1- related CARD-only proteins. Biochem. Soc. Trans. 35, 1508–1511 (2007).
Vercammen, D. et al. Inhibition of caspases increases the sensitivity of L929 cells to necrosis mediated by tumor necrosis factor. J. Exp. Med. 187, 1477–1485 (1998).
Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 (2000).
Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).
Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat. Chem. Biol. 4, 313–321 (2008).
Kelliher, M. A. et al. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297–303 (1998). Reference 155 identifies RIPK1 as a major adaptor for the activation of NF- κ B upon TNFR1 ligation. Reference 154 identifies RIPK1 as an effector of necroptosis. Together, these two papers establish that RIPK1 is at the crossroads of cell death and inflammation.
Ea, C.-K., Deng, L., Xia, Z.-P., Pineda, G. & Chen, Z. J. Activation of IKK by TNFα requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 22, 245–257 (2006).
Zhang, D.-W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).
Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1–RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).
He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111 (2009).
Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012).
Zhao, J. et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl Acad. Sci. USA 109, 5322–5327 (2012).
Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65 (2014).
Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).
Murphy, J. M. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443–453 (2013).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).
Chan, F. K.-M., Luz, N. F. & Moriwaki, K. Programmed necrosis in the cross talk of cell death and inflammation. Annu. Rev. Immunol. 33, 79–106 (2015).
Paquette, N. et al. Caspase-mediated cleavage, IAP binding, and ubiquitination: linking three mechanisms crucial for Drosophila NF-κB signaling. Mol. Cell 37, 172–182 (2010).
Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13, 2514–2526 (1999).
Georgel, P. et al. Drosophila immune deficiency (IMD) is a death domain protein that activates antibacterial defense and can promote apoptosis. Dev. Cell 1, 503–514 (2001).
Chan, F. K., Luz, N. F. & Moriwaki, K. Programmed necrosis in the cross talk of cell death and inflammation. Annu. Rev. Immunol. 33, 79–106 (2015).
Chen, W. et al. Ppm1b negatively regulates necroptosis through dephosphorylating Rip3. Nat. Cell Biol. 17, 434–444 (2015).
Onizawa, M. et al. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat. Immunol. 16, 618–627 (2015).
Bevan, M. J. Antigen recognition. Class discrimination in the world of immunology. Nature 325, 192–194 (1987).
Janeway, C. A. Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54, 1–13 (1989).
Huang, A. Y. et al. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264, 961–965 (1994).
Stanger, B. Z., Leder, P., Lee, T. H., Kim, E. & Seed, B. RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death. Cell 81, 513–523 (1995).
Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell 10, 417–426 (2002). This study defines the inflammasome as a platform that regulates caspase 1 activation and IL-1 β maturation and release. It is one of the first studies to elucidate a common molecular pathway for the simultaneous induction of cell death and inflammation.
The authors thank I. Mellman for critical reading of the manuscript, and the reviewers for their constructive feedback and suggestions. They also thank the Agence Nationale de la Recherche, France, and the Liliane Bettencourt School of INSERM, Paris, France, for their support of this work.
The authors declare no competing financial interests.
Substances or molecules that are capable of binding to an antibody or a T cell receptor.
A functional outcome of cross-presentation, whereby antigen-specific naive CD8+ T cells are activated to become cytotoxic T lymphocytes. To be fully activated, CD8+ T cells require at least three signals. Cross-priming is essential for tumour immunity, autoimmunity and viral immunity in instances in which the antigens are not endogenously synthesized by dendritic cells.
The presentation of extracellular antigens on MHC class I molecules, which may be contrasted with the presentation of endogenously synthesized antigens via the conventional pathway. Cross-presentation is a function of antigen-presenting cells that have the machinery to capture, process and cross-present extracellular antigens. It can result in either cross-priming or cross-tolerance.
A functional outcome of cross-presentation, whereby antigen-specific naive CD8+ T cells are deleted or rendered tolerant. To become tolerized, CD8+ T cells must be engaged in the absence of an activation signal (that is, signal 3). Cross-tolerance is essential for achieving tolerance to antigen that is uniquely expressed by peripheral tissue or by foreign tissues such as the fetus and transplanted tissue.
- Pathogen-associated molecular patterns
(PAMPs). Molecular motifs that are associated with classes of pathogen and are capable of ligating innate immune receptors known as pattern recognition receptors.
- Signal 0
The engagement of host sensors that results in the activation of antigen-presenting cells. Stimulation may occur by triggering surface, endosomal or cytosolic pathogen recognition receptors.
- Licensing model
A term coined by Antonio Lanzevecchia to refer to the engagement of CD40 (or other activation receptors) on dendritic cells, which in turn results in the release of signal 3 — a signal that acts on T cells and is required for CD8+ T cell priming.
A morphological definition of cell death characterized by the loss of plasma membrane integrity. The term is classically used to refer to accidental cell death, but it also describes late apoptotic cells that have not been cleared and have secondarily lost plasma membrane integrity (that is, cells that have undergone secondary necrosis).
- Signal −1
A signal that originates in the antigen-donor cell as a result of cell stress and death. Effector pathways that lead to cell death (for example, activation of receptor-interacting protein kinase 1 and nuclear factor-κB) also signal innate immunity. The activation of innate immunity pathways within dying cells is an initiating immunological signal that we term signal −1.
A substance or a molecule that has the ability to induce an adaptive immune response.
A morphological definition of cell death that is characterized by membrane blebbing and the formation of apoptotic bodies. Several pathways of apoptosis have been described, all of which are dependent on the activation ofinitiator and executioner caspases. Apoptosis can be immunologically silent, inflammatory and/or immunogenic.
- Microbe-associated molecular patterns
(MAMPs). The term 'pathogen-associated molecular patterns' has been challenged by the fact that most microorganisms are not pathogenic, yet they express molecules that engage pattern recognition receptors; the term 'MAMPs' has therefore been suggested and is the preferred term used in this Review.
- Inflammatory cell death
A setting in which dying cells induce an inflammatory response, such as the activation and recruitment of innate immune cells, including neutrophils and monocytes. Inflammatory cell death should not be confused with immunogenic cell death.
- Immunogenic cell death
A setting in which dying cells induce an adaptive immune response, and provide both antigen and immune-stimulatory molecules.
An energy-dependent, genetically encoded form of necrosis that is dependent on signalling via receptor-interacting protein kinase 3 and mixed lineage kinase domain-like protein.
An energy-dependent, genetically encoded form of necrosis that is dependent on the activation of caspases such as caspase 1 and/or caspase 11. Downstream of caspase activation, gasdermin D is capable of mediating membrane permeabilization.
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Yatim, N., Cullen, S. & Albert, M. Dying cells actively regulate adaptive immune responses. Nat Rev Immunol 17, 262–275 (2017). https://doi.org/10.1038/nri.2017.9
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