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• W2074401812 abstract "The mammalian immune system continually faces death in the form of its own dead and dying cells that arise during normal tissue turnover, infections, cellular damage, and cancer. Complex decisions must then be made that will permit a protective response to pathogens, while at the same time destroying tumors but not attacking vital systems of the host that could lead to autoimmunity. By using an investigative technique termed the five Ws (who, what, when, where, and why), we will examine how the immune system responds to antigens generated via cell death. This analysis will give us a better understanding of the molecular differences fundamental to tolerogenic or immunogenic cell death, the cells that sense and react to the dead cells, and the consequences of these fundamental elements on the maintenance or abrogation of tolerance. The mammalian immune system continually faces death in the form of its own dead and dying cells that arise during normal tissue turnover, infections, cellular damage, and cancer. Complex decisions must then be made that will permit a protective response to pathogens, while at the same time destroying tumors but not attacking vital systems of the host that could lead to autoimmunity. By using an investigative technique termed the five Ws (who, what, when, where, and why), we will examine how the immune system responds to antigens generated via cell death. This analysis will give us a better understanding of the molecular differences fundamental to tolerogenic or immunogenic cell death, the cells that sense and react to the dead cells, and the consequences of these fundamental elements on the maintenance or abrogation of tolerance. A variety of pathways are used by multicellular organisms to orchestrate cell death during development and morphogenesis to control cell numbers and eliminate damaged cells (Penaloza et al., 2006Penaloza C. Lin L. Lockshin R.A. Zakeri Z. Cell death in development: shaping the embryo.Histochem. Cell Biol. 2006; 126: 149-158Crossref PubMed Scopus (48) Google Scholar). It is estimated that up to 106 cells die in the human body every second, most as a result of normal tissue turnover (Green et al., 2009Green D.R. Ferguson T. Zitvogel L. Kroemer G. Immunogenic and tolerogenic cell death.Nat. Rev. Immunol. 2009; 9: 353-363Crossref PubMed Scopus (246) Google Scholar). There is also cell death in response to infection that may represent a primitive defense mechanism to prevent pathogen replication by removing the infected or damaged cells. Moreover, the same cell death pathways are needed to control the number of effector cells generated during an immune response and then eliminate the majority of them once the pathogen is cleared (Parish et al., 2009Parish I.A. Rao S. Smyth G.K. Juelich T. Denyer G.S. Davey G.M. Strasser A. Heath W.R. The molecular signature of CD8+ T cells undergoing deletional tolerance.Blood. 2009; 113: 4575-4585Crossref PubMed Scopus (21) Google Scholar, Pellegrini et al., 2003Pellegrini M. Belz G. Bouillet P. Strasser A. Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim.Proc. Natl. Acad. Sci. USA. 2003; 100: 14175-14180Crossref PubMed Scopus (156) Google Scholar, Barreiro et al., 2004Barreiro R. Luker G. Herndon J. Ferguson T.A. Termination of antigen-specific immunity by CD95 ligand (Fas ligand) and IL-10.J. Immunol. 2004; 173: 1519-1525PubMed Google Scholar). Thus, one of the major challenges for the immune system is to react to foreign pathogens within the context of this constant antigenic “noise” derived from the dead and dying cells, yet not respond to the self-antigens that can be presented to the immune system in far greater (and uncontrollable) amounts. Simultaneously, it is advantageous to retain the ability to direct immune responses toward the “self” antigens expressed by tumor cells. Thus, the immune system is faced with the important task of being responsive to pathogens (foreign invaders) while destroying tumors (derived from self) and not attacking vital systems of the host (self-antigens). Understanding how these complex immunological decisions are made has been intensely investigated over the past 20 years, although it has been difficult, at times, to get the complete picture. One reason for this is that each study focused on only a few criteria that may not apply in every situation. For example, the general mechanism by which a cell died was proposed to influence the type of immune response. This concept arose from some of the original descriptions of apoptosis as being a “silent death” and tolerogenic, whereas necrosis was a “violent death” that released a number of immunostimulatory molecules (Green et al., 2009Green D.R. Ferguson T. Zitvogel L. Kroemer G. Immunogenic and tolerogenic cell death.Nat. Rev. Immunol. 2009; 9: 353-363Crossref PubMed Scopus (246) Google Scholar, Thompson, 1995Thompson C.B. Apoptosis in the pathogenesis and treatment of disease.Science. 1995; 267: 1456-1462Crossref PubMed Google Scholar). In some instances this has proven true as demonstrated by studies comparing the tolerogenic and immunogenic properties of apoptotic and necrotic cells (Griffith et al., 1996Griffith 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. 1996; 5: 7-16Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, Griffith et al., 2007Griffith T.S. Kazama H. VanOosten R.L. Earle Jr., J.K. Herndon J.M. Green D.R. Ferguson T.A. Apoptotic cells induce tolerance by generating helpless CD8+ T cells that produce TRAIL.J. Immunol. 2007; 178: 2679-2687PubMed Google Scholar, Shi et al., 2003Shi Y. Evans J.E. Rock K.L. Molecular identification of a danger signal that alerts the immune system to dying cells.Nature. 2003; 425: 516-521Crossref PubMed Scopus (853) Google Scholar). It is now recognized, however, that apoptotic cells can be highly immunogenic, eliciting protective immune responses (Kepp et al., 2009Kepp O. Tesniere A. Schlemmer F. Michaud M. Senovilla L. Zitvogel L. Kroemer G. Immunogenic cell death modalities and their impact on cancer treatment.Apoptosis. 2009; 14: 364-375Crossref PubMed Scopus (76) Google Scholar, Ullrich et al., 2008Ullrich E. Bonmort M. Mignot G. Kroemer G. Zitvogel L. Tumor stress, cell death and the ensuing immune response.Cell Death Differ. 2008; 15: 21-28Crossref PubMed Scopus (47) Google Scholar, Zitvogel et al., 2004Zitvogel L. Casares N. Péquignot M.O. Chaput N. Albert M.L. Kroemer G. Immune response against dying tumor cells.Adv. Immunol. 2004; 84: 131-179Crossref PubMed Scopus (72) Google Scholar). In an effort to explain this disparity, some studies have characterized the molecular composition of dying cells, suggesting that factors released at the time of cell death could determine the resultant immune response. For example, the release of cytokines or damage-associated molecular patterns (DAMPs) from a dying cell can influence immunity (Bianchi, 2007Bianchi M.E. DAMPs, PAMPs and alarmins: all we need to know about danger.J. Leukoc. Biol. 2007; 81: 1-5Crossref PubMed Scopus (762) Google Scholar, Chen et al., 2001Chen W. Frank M.E. Jin W. Wahl S.M. TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu.Immunity. 2001; 14: 715-725Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, Gao et al., 1998Gao Y. Herndon J.M. Zhang H. Griffith T.S. Ferguson T.A. Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis.J. Exp. Med. 1998; 188: 887-896Crossref PubMed Scopus (155) Google Scholar, Millar et al., 2003Millar D.G. Garza K.M. Odermatt B. Elford A.R. Ono N. Li Z. Ohashi P.S. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo.Nat. Med. 2003; 9: 1469-1476Crossref PubMed Scopus (175) Google Scholar). Although these studies are compelling, the release of factors from dying cells does not always dictate the type of immune response, because DAMPs can be modified by the cell death pathway to promote either tolerance or immunity (Kazama et al., 2008Kazama H. Ricci J.E. Herndon J.M. Hoppe G. Green D.R. Ferguson T.A. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.Immunity. 2008; 29: 21-32Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Another approach has considered the activation of phagocytic cells as the deciding factor in the generation of tolerance or immunity to the antigens associated with the eaten dead cells. These data suggest that dead cells (apoptotic or necrotic) can inhibit or increase antigen presentation by the antigen-presenting cell (APC) (Albert et al., 2001Albert M.L. Jegathesan M. Darnell R.B. Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells.Nat. Immunol. 2001; 2: 1010-1017Crossref PubMed Scopus (301) Google Scholar, Dhodapkar et al., 2001Dhodapkar M.V. Steinman R.M. Krasovsky J. Munz C. Bhardwaj N. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells.J. Exp. Med. 2001; 193: 233-238Crossref PubMed Scopus (1005) Google Scholar, Sauter et al., 2000Sauter B. Albert M.L. Francisco L. Larsson M. Somersan S. Bhardwaj N. 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; 191: 423-434Crossref PubMed Scopus (978) Google Scholar). However, it is important to keep in mind that the maturation state of the phagocyte does not always dictate its ability to induce tolerance or immunity (Ferguson et al., 2002Ferguson T.A. Herndon J. Elzey B. Griffith T.S. Schoenberger S. Green D.R. Uptake of apoptotic antigen-coupled cells by lymphoid dendritic cells and cross-priming of CD8(+) T cells produce active immune unresponsiveness.J. Immunol. 2002; 168: 5589-5595PubMed Google Scholar, Kazama et al., 2008Kazama H. Ricci J.E. Herndon J.M. Hoppe G. Green D.R. Ferguson T.A. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.Immunity. 2008; 29: 21-32Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). To reconcile some of these disparities, the influence of pathogen-associated molecular patterns (PAMPs) derived from infectious agents has also been considered, because bacterial products or viral nucleic acids perceived by phagocytic cells in the presence of dead cells can dictate the resultant immune response through activation of APC (Medzhitov and Janeway, 2002Medzhitov R. Janeway Jr., C.A. Decoding the patterns of self and nonself by the innate immune system.Science. 2002; 296: 298-300Crossref PubMed Scopus (962) Google Scholar, Torchinsky et al., 2009Torchinsky M.B. Garaude J. Martin A.P. Blander J.M. Innate immune recognition of infected apoptotic cells directs T(H)17 cell differentiation.Nature. 2009; 458: 78-82Crossref PubMed Scopus (139) Google Scholar). This hypothesis, too, has been questioned by observations where the death of transformed cells (Obeid et al., 2007Obeid M. Tesniere A. Ghiringhelli F. Fimia G.M. Apetoh L. Perfettini J.L. Castedo M. Mignot G. Panaretakis T. Casares N. et al.Calreticulin exposure dictates the immunogenicity of cancer cell death.Nat. Med. 2007; 13: 54-61Crossref PubMed Scopus (633) Google Scholar) and in some cases nontransformed cells (Rock and Kono, 2008Rock K.L. Kono H. The inflammatory response to cell death.Annu. Rev. Pathol. 2008; 3: 99-126Crossref PubMed Scopus (141) Google Scholar, Shi et al., 2003Shi Y. Evans J.E. Rock K.L. Molecular identification of a danger signal that alerts the immune system to dying cells.Nature. 2003; 425: 516-521Crossref PubMed Scopus (853) Google Scholar) elicited immune responses in the absence of infection. In addition, debris from nontransformed cells in some settings can stimulate general or organ-specific autoimmune responses (Gaipl et al., 2007Gaipl U.S. Munoz L.E. Grossmayer G. Lauber K. Franz S. Sarter K. Voll R.E. Winkler T. Kuhn A. Kalden J. et al.Clearance deficiency and systemic lupus erythematosus (SLE).J. Autoimmun. 2007; 28: 114-121Crossref PubMed Scopus (118) Google Scholar). Thus, a simple explanation based on any of these criteria cannot apply to all aspects of tolerogenic and immunogenic cell death. As important as it is to consider the factors listed above, it is equally important to consider those criteria that are not typically discussed in this context—including variations in the type of dead cell (e.g., lymphocyte, fibroblast, epithelial cell), cell status (transformed, nontransformed, activated, naive), immune response examined (humoral or cellular), organ or organ system explored (e.g., gut, eye, skin), availability of T cell help, and even the desired result (e.g., graft acceptance, antitumor immunity, autoimmunity, immune deviation). With the addition of these many considerations (and caveats), it becomes even more difficult to apply general principles to every situation. We certainly cannot consider all of these variables in this review, but we think it is important to keep them in mind as we discuss the effects of cell death on the immune response. Consequently, for our discussion we have applied (and slightly modified) the old journalism maxim called the “five Ws.” This is a classical concept in news style, research, and police investigations such that for a report to be considered complete it must answer a checklist of questions—who, what, when, where, why, and how. Thus, the nature of the immune response that develops in the face of dead cells depends on who dies, what it releases, when it dies, where it dies, and why it dies. The answers to these questions lead us to an understanding of how immunity is regulated. With these interrogative questions we can perhaps get a better understanding of the molecular differences fundamental to tolerogenic or immunogenic cell death, the cells that sense and react to the dead cells, and the consequences of these fundamental elements on the maintenance or abrogation of tolerance. Variations in these factors can have consequences that range from effective antipathogen or antitumor immune responses to autoimmune pathology. Just as different types of living cells are highly specialized to perform unique functions, the type of cell dying can dramatically influence the resultant immune response. For example, bortezomib-induced apoptotic myeloma cells expose the chaperone HSP90 on their surface, facilitating their recognition by dendritic cells (DCs) and the subsequent induction of immunity (Spisek et al., 2007Spisek R. Charalambous A. Mazumder A. Vesole D.H. Jagannath S. Dhodapkar M.V. 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; 109: 4839-4845Crossref PubMed Scopus (116) Google Scholar). Similarly, in response to some chemotherapeutics (such as anthracyclins), but not others (such as mitomycin C or etoposide), tumor cells expose complexes formed by the chaperone calreticulin and disulphide isomerase eRp57 on their cell surface. This occurs at a proapoptotic stage and facilitates the uptake of dying cells by DCs (Obeid et al., 2007Obeid M. Tesniere A. Ghiringhelli F. Fimia G.M. Apetoh L. Perfettini J.L. Castedo M. Mignot G. Panaretakis T. Casares N. et al.Calreticulin exposure dictates the immunogenicity of cancer cell death.Nat. Med. 2007; 13: 54-61Crossref PubMed Scopus (633) Google Scholar, Panaretakis et al., 2008Panaretakis T. Joza N. Modjtahedi N. Tesniere A. Vitale I. Durchschlag M. Fimia G.M. Kepp O. Piacentini M. Froehlich K.U. et al.The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death.Cell Death Differ. 2008; 15: 1499-1509Crossref PubMed Scopus (102) Google Scholar). Exposure of these complexes strongly correlates with immunogenicity, and anthracyclin-treated dying tumor cells that expose calreticulin can be used as a cancer vaccine. Because this cell death is caspase dependent and apoptotic, this is an example where apoptotic death can prime for immunity. In contrast, Ronchetti et al., 1999aRonchetti A. Iezzi G. Crosti M.C. Garancini M.P. Protti M.P. Bellone M. Role of antigen-presenting cells in cross-priming of cytotoxic T lymphocytes by apoptotic cells.J. Leukoc. Biol. 1999; 66: 247-251PubMed Google Scholar, Ronchetti et al., 1999bRonchetti A. Rovere P. Iezzi G. Galati G. Heltai S. Protti M.P. Garancini M.P. Manfredi A.A. Rugarli C. Bellone M. Immunogenicity of apoptotic cells in vivo: role of antigen load, antigen-presenting cells, and cytokines.J. Immunol. 1999; 163: 130-136PubMed Google Scholar found that although apoptotic tumor cells could prime, they were much less efficient than nonreplicating live cells. The immunogenicity of the apoptotic cells was proportional to the number of cells injected and correlated with the serum concentration of interleukin-10 (IL-10) and interleukin-1 beta (IL-1β). Another study found that DCs (but not macrophages [Mϕ]) pulsed with apoptotic tumor cells were efficient at cross-priming (immunity) (Miyake et al., 2007Miyake Y. Asano K. Kaise H. Uemura M. Nakayama M. Tanaka M. Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens.J. Clin. Invest. 2007; 117: 2268-2278Crossref PubMed Scopus (78) Google Scholar), highlighting the importance of the cell phagocytizing the dead cells (see “Where” below). Interestingly, γ-irradiated tumor cells can also be tolerogenic based on their ability to suppress cytotoxic T lymphocyte (CTL) responses and antitumor immunity via the induction of CD8+ T cell anergy and CD4+ regulatory T (Treg) cell responses (Xie et al., 2009Xie Y. Bai O. Yuan J. Chibbar R. Slattery K. Wei Y. Deng Y. Xiang J. Tumor apoptotic bodies inhibit CTL responses and antitumor immunity via membrane-bound transforming growth factor-beta1 inducing CD8+ T-cell anergy and CD4+ Tr1 cell responses.Cancer Res. 2009; 69: 7756-7766Crossref PubMed Scopus (15) Google Scholar). Thus, apoptotic tumor cells can prime or tolerize depending on other factors (see “What” below) or the experimental system (or tumor type) employed. In contrast, a recent study suggests that in some situations live tumor cells may represent a more efficient method of priming the immune system compared to dead cells (Matheoud et al., 2010Matheoud D. Perié L. Hoeffel G. Vimeux L. Parent I. Marañón C. Bourdoncle P. Renia L. Prevost-Blondel A. Lucas B. et al.Cross-presentation by dendritic cells from live cells induces protective immune responses in vivo.Blood. 2010; 115: 4412-4420Crossref PubMed Scopus (17) Google Scholar). These authors found that DCs internalized cytosolic and membrane material into vesicles from metabolically labeled live cells, leading to enhanced cross-priming (immunity). It has been suggested that the death of tissue cells during normal cell turnover followed by their uptake by resident DCs is involved in the maintenance of peripheral tolerance (Luckashenak et al., 2008Luckashenak N. Schroeder S. Endt K. Schmidt D. Mahnke K. Bachmann M.F. Marconi P. Deeg C.A. Brocker T. Constitutive crosspresentation of tissue antigens by dendritic cells controls CD8+ T cell tolerance in vivo.Immunity. 2008; 28: 521-532Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar). Several studies have addressed this issue with systems where model antigens were overexpressed in defined cells from birth such that they were considered “self-antigens” by the immune system. In these instances, potent tolerance could be induced to these experimental self-antigens (Adler et al., 1998Adler A.J. Marsh D.W. Yochum G.S. Guzzo J.L. Nigam A. Nelson W.G. Pardoll D.M. CD4+ T cell tolerance to parenchymal self-antigens requires presentation by bone marrow-derived antigen-presenting cells.J. Exp. Med. 1998; 187: 1555-1564Crossref PubMed Scopus (218) Google Scholar, Kurts et al., 1998Kurts C. Heath W.R. Kosaka H. Miller J.F. Carbone F.R. The peripheral deletion of autoreactive CD8+ T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1).J. Exp. Med. 1998; 188: 415-420Crossref PubMed Scopus (120) Google Scholar). Similarly, experiments with nontransformed cells such as pancreatic islets demonstrate that apoptotic death can make these cells efficient tolerogens. Young nonobese diabetic (NOD) mice injected with a single low dose of streptozotocin exhibited impaired T cell responses and mice were protected from spontaneous diabetes. β-cell apoptosis was necessary for this tolerance, because streptozotocin did not protect rat insulin promoter-cytokine response modifier A (RIP-CrmA) transgenic NOD mice (Hugues et al., 2002Hugues S. Mougneau E. Ferlin W. Jeske D. Hofman P. Homann D. Beaudoin L. Schrike C. Von Herrath M. Lehuen A. Glaichenhaus N. Tolerance to islet antigens and prevention from diabetes induced by limited apoptosis of pancreatic beta cells.Immunity. 2002; 16: 169-181Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Similarly, DCs fed apoptotic islet cells induced potent tolerance and prevented the development of diabetes in the recipients when injected (Marin-Gallen et al., 2010Marin-Gallen S. Clemente-Casares X. Planas R. Pujol-Autonell I. Carrascal J. Carrillo J. Ampudia R. Verdaguer J. Pujol-Borrell R. Borràs F.E. Vives-Pi M. Dendritic cells pulsed with antigen-specific apoptotic bodies prevent experimental type 1 diabetes.Clin. Exp. Immunol. 2010; 160: 207-214Crossref PubMed Scopus (13) Google Scholar). The death of T cells during activation-induced cell death (AICD) can also induce potent tolerance, not just by deleting the reactive cells but also by generating active regulatory cells (Herndon et al., 2005Herndon 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. 2005; 174: 4098-4104PubMed Google Scholar, Gurung et al., 2010Gurung P. Kucaba T.A. Schoenberger S.P. Ferguson T.A. Griffith T.S. TRAIL-expressing CD8+ T cells mediate tolerance following soluble peptide-induced peripheral T cell deletion.J. Leukoc. Biol. 2010; 88: 1217-1225Crossref PubMed Scopus (7) Google Scholar). In this situation, tolerance was directed only to T cells of the same specificity, perhaps to control potential autoimmunity during the contraction phase of an immune response where large numbers of antigen-reactive T cells were deleted. In a similar manner, treatment of normal mice with intact antibody to CD3 (which induces tolerance) increases systemic TGF-β produced by Mϕ and immature DC phagocytes exposed to apoptotic T cells leading to immune suppression (Perruche et al., 2008Perruche S. Zhang P. Liu Y. Saas P. Bluestone J.A. Chen W. CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells.Nat. Med. 2008; 14: 528-535Crossref PubMed Scopus (91) Google Scholar). In contrast, in vitro anti-CD3-activated normal T cells induced to undergo apoptosis are immunogenic, not tolerogenic—an effect mediated by CD154 expression on the activated T cell (Gurung et al., 2009Gurung P. Kucaba T.A. Ferguson T.A. Griffith T.S. Activation-induced CD154 expression abrogates tolerance induced by apoptotic cells.J. Immunol. 2009; 183: 6114-6123Crossref PubMed Scopus (11) Google Scholar). Similarly, activated γ-irradiated peripheral blood mononuclear cells (PBMC) will mature human DCs, leading to the production of proinflammatory cytokines (Johansson et al., 2007Johansson 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. 2007; 179: 1711-1720PubMed Google Scholar). The question then becomes why do apoptotic T cells in some cases induce tolerance but in others promote immunity? The answer may lie with the timing of the T cell death (see “When” below). Perhaps when small numbers of dying cells arise during normal turnover they are ignored by the immune system. Regardless, different types of dying cells can induce dramatically different immune responses, making it difficult to predict the outcome and leading us to consider what are the dying cells releasing as the next important factor. Several mechanisms have been proposed to explain the intrinsic tolerogenic and immunogenic potential of dead cells, including the elaboration of cytokines, DAMPs, and other cellular proteins. Apoptotic lymphocytes produce the immunosuppressive cytokines IL-10 (Gao et al., 1998Gao Y. Herndon J.M. Zhang H. Griffith T.S. Ferguson T.A. Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis.J. Exp. Med. 1998; 188: 887-896Crossref PubMed Scopus (155) Google Scholar) and TGF-β (Chen et al., 2001Chen W. Frank M.E. Jin W. Wahl S.M. TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu.Immunity. 2001; 14: 715-725Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar) as they die. In contrast, DAMPs, such as HMGB1 (Kazama et al., 2008Kazama H. Ricci J.E. Herndon J.M. Hoppe G. Green D.R. Ferguson T.A. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.Immunity. 2008; 29: 21-32Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar, Scaffidi et al., 2002Scaffidi P. Misteli T. Bianchi M.E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation.Nature. 2002; 418: 191-195Crossref PubMed Scopus (1557) Google Scholar), heat shock proteins (e.g., HSP70) (Millar et al., 2003Millar D.G. Garza K.M. Odermatt B. Elford A.R. Ono N. Li Z. Ohashi P.S. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo.Nat. Med. 2003; 9: 1469-1476Crossref PubMed Scopus (175) Google Scholar), uric acid (Shi et al., 2003Shi Y. Evans J.E. Rock K.L. Molecular identification of a danger signal that alerts the immune system to dying cells.Nature. 2003; 425: 516-521Crossref PubMed Scopus (853) Google Scholar), mammalian DNA, RNA, IFN-α (Matzinger, 2002Matzinger P. The danger model: a renewed sense of self.Science. 2002; 296: 301-305Crossref PubMed Scopus (1939) Google Scholar), and CD154 (Gurung et al., 2009Gurung P. Kucaba T.A. Ferguson T.A. Griffith T.S. Activation-induced CD154 expression abrogates tolerance induced by apoptotic cells.J. Immunol. 2009; 183: 6114-6123Crossref PubMed Scopus (11) Google Scholar), released by dead cells are immunogenic. Recognition of DAMPs (e.g., HMGB1) by pattern recognition receptors (PRR) such as the receptor for advance glycation end products (RAGE) or toll-like receptors (TLRs) is thought to mature DCs and stimulate immunity (Bianchi, 2007Bianchi M.E. DAMPs, PAMPs and alarmins: all we need to know about danger.J. Leukoc. Biol. 2007; 81: 1-5Crossref PubMed Scopus (762) Google Scholar). In addition, necrotic cells can activate the inflammasome (immunity), as shown by the cleavage of caspase 1 and release of mature IL-1β and IL-18 (Lamkanfi and Dixit, 2010Lamkanfi M. Dixit V.M. Manipulation of host cell death pathways during microbial infections.Cell Host Microbe. 2010; 8: 44-54Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, Li et al., 2009Li H. Ambade A. Re F. Cutting edge: Necrosis activates the NLRP3 inflammasome.J. Immunol. 2009; 183: 1528-1532Crossref PubMed Scopus (59) Google Scholar). Thus, the different mechanisms of death along with the production and/or release of various pro- and anti-inflammatory molecules as a result of the death process all contribute to whether immunological tolerance or immunity is initiated against the antigens associated with the dead cells. Interestingly, the release of “factors” is not always predictive because the cell death process itself can alter the immunogenicity of the molecules released. All apoptotic cells can release DAMPs (Choi et al., 2004Choi J.J. Reich 3rd, C.F. Pisetsky D.S. Release of DNA from dead and dying lymphocyte and monocyte cell lines in vitro.Scand. J. Immunol. 2004; 60: 159-166Crossref PubMed Scopus (37) Google Scholar, Kazama et al., 2008Kazama H. Ricci J.E. Herndon J.M. Hoppe G. Green D.R. Ferguson T.A. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.Immunity. 2008; 29: 21-32Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar), but the process of apoptosis can modify these immunostimulatory molecules to promote tolerance instead of immunity (Kazama et al., 2008Kazama H. Ricci J.E. Herndon J.M. Hoppe G. Green D.R. Ferguson T.A. Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein.Immunity. 2008; 29: 21-32Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). For example, intravenously injected necrotic cells promote antigen-specific immune responses through a mechanism that involves the release of HMGB1; in the absence of active HMGB1, these cells induce tolerance. Similarly, apoptotic cells can be immunogenic rather than tolerogenic if caspase activation is blocked or caspase-3 and -7 are absent. This seems to contradict the requirement for caspase activation in immunogenic cell death by anthracyclin-treated tumor cells (Zitvogel et al., 2004Zitvogel L. Casares N. Péquignot M.O. Chaput N. Albert M.L. Kroemer G. Immune response against dying tumor cells.Adv. Immunol. 2004; 84: 131-179Crossref PubMed Scopus (72) Google Scholar) (discussed above), but perhap" @default.
• W2074401812 created "2016-06-24" @default.
• W2074401812 creator A5030800645 @default.
• W2074401812 creator A5076681768 @default.
• W2074401812 date "2011-10-01" @default.
• W2074401812 modified "2023-10-18" @default.
• W2074401812 title "Cell Death in the Maintenance and Abrogation of Tolerance: The Five Ws of Dying Cells" @default.
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