Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

A blast from the past: clearance of apoptotic cells regulates immune responses

Nature Reviews Immunology volume 2, pages 965–975 (2002)Cite this article

Key Points

  • Apoptosis, a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes. However, the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by inducing or suppressing inflammation. Therefore, dead cells, which are a reflection of an organism's immediate past, can control its immunological future.

  • Dying cells are recognized by phagocytes as being non-self, altered-self or non-motile self, using innate-immune recognition, scavenger receptors or immunoglobulin-superfamily molecules, respectively.

  • Cell clearance by apoptosis has anti-inflammatory properties, by suppressing the release of pro-inflammatory cytokines by monocytes/macrophages and by the direct release of immunosuppressive cytokines, such as interleukin-10 and transforming growth factor-β1, by apoptotic cells.

  • Dendritic-cell maturation and presentation of antigen are suppressed by the uptake of apoptotic cells, which leads to the promotion of tolerance.

  • Defects in the clearance of apoptotic cells are associated with spontaneous/persistent tissue inflammation and autoimmunity to cell contents.

  • Strategies to promote the safe, anti-inflammatory and immunosuppressive clearance of dying cells are discussed.

  • There is a need to understand the mechanisms that, under certain circumstances, paradoxically allow apoptotic cells to stimulate the release of pro-inflammatory cytokines, such as tumour-necrosis factor, by macrophages and that allow dendritic cells to present antigen derived from apoptotic cells.

Abstract

Apoptosis, which is a programmed and physiological form of cell death, is known to shape the immune system by regulating populations of effector lymphocytes. However, the binding and ingestion of dying cells by monocytes/macrophages and dendritic cells can also influence immune responses markedly by enhancing or suppressing inflammation. Therefore, dead cells, which are a reflection of an organism's immediate past, can control its immunological future.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Three classes of mechanism for the recognition of apoptotic cells by phagocytes.
Figure 2: Virtual colour-scanning electron micrograph of phagocyte sampling of the surface of an apoptotic cell.
Figure 3: Two classes of mechanism for apoptotic-cell suppression of phagocyte pro-inflammatory responses.
Figure 4: Simple model of the modulation of dendritic-cell maturation by ingestion of apoptotic cells.

Similar content being viewed by others

References

  1. Kerr, J. F. R., Wyllie, A. H. & Currie, A. R. Apoptosis: a basic biological phenomenon with widespread implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972). The seminal description of apoptosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Krammer, P. H. CD95's deadly mission in the immune system. Nature 407, 789–795 (2000).

    CAS  PubMed  Google Scholar 

  3. Savill, J. & Fadok, V. Corpse clearance defines the meaning of cell death. Nature 407, 784–788 (2000).

    CAS  PubMed  Google Scholar 

  4. Taylor, P. R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells. J. Exp. Med. 192, 359–366 (2000). A crucial demonstration of the links between defective clearance of apoptotic cells and autoimmunity (see also reference 103).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 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). The first report of mechanisms by which antigens that are expressed by apoptotic cells can be presented to T cells, thereby accounting for cross-presentation.

    CAS  PubMed  Google Scholar 

  6. Savill, J. S., Dransfield, I., Hogg, N. & Haslett, C. Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature 343, 170–173 (1990). A description of the first phagocyte receptor for apoptotic cells to be identified, as shown by antibody- and peptide-mediated blockade and the selection of vitronectin-receptor-bearing macrophages.

    CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hu, B., Sonstein, J., Christensen, P. J., Punturieri, A. & Curtis, J. L. Deficient in vitro and in vivo phagocytosis of apoptotic T cells by resident murine alveolar macrophages. J. Immunol. 165, 2124–2133 (2000).

    CAS  PubMed  Google Scholar 

  9. Schagat, T. L., Wofford, J. A. & Wright, J. R. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils. J. Immunol. 166, 2727–2733 (2001).

    CAS  PubMed  Google Scholar 

  10. Mevorach, D., Mascarenhas, J. O., Gershov, D. & Elkon, K. B. Complement-dependent clearance of apoptotic cells by human macrophages. J. Exp. Med. 188, 2313–2320 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Gaipl, U. S. et al. Complement binding is an early feature of necrotic and a rather late event during apoptotic cell death. Cell Death Differ. 8, 327–334 (2001).

    CAS  PubMed  Google Scholar 

  12. Savill, J. S., Henson, P. M. & Haslett, C. Phagocytosis of aged human neutrophils by macrophages is mediated by a novel 'charge-sensitive' recognition mechanism. J. Clin. Invest. 84, 1518–1527 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ren, Y. et al. Non-phlogistic clearance of late apoptotic neutrophils by macrophages: efficient phagocytosis independent of β2-integrins. J. Immunol. 166, 4743–4750 (2001).

    CAS  PubMed  Google Scholar 

  14. Scott, R. S. et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207–211 (2001). The first data to indicate a role in the phagocytosis of apoptotic cells for receptor tyrosine kinases that normally keep immune responses in check (see also reference 104).

    CAS  PubMed  Google Scholar 

  15. Hamon, Y. et al. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nature Cell Biol. 2, 399–406 (2000). An important demonstration of a role for the CED7 homologue ABC1 in altering plasma-membrane lipid distribution in dying cells and phagocytes to promote the clearance of apoptotic cells in vitro and in vivo (see also reference 37).

    CAS  PubMed  Google Scholar 

  16. Pickering, M. C. et al. Ultraviolet radiation-induced keratinocyte apoptosis in C1q-deficient mice. J. Invest. Dermatol. 117, 52–58 (2001).

    CAS  PubMed  Google Scholar 

  17. Ogden, C. A. et al. C1q and mannose-binding lectin engagement of cell-surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781–795 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Devitt, A. et al. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392, 505–509 (1998). A pioneering report implicating recognition mechanisms of innate immunity in the clearance of dying cells.

    CAS  PubMed  Google Scholar 

  19. Savill, J. Apoptosis: phagocytic docking without shocking. Nature 392, 442–443 (1998).

    CAS  PubMed  Google Scholar 

  20. Gershov, D., Kim, S., Brot, N. & Elkon, K. B. C-reactive protein binds to apoptotic cells, protects the cells from assembly of the terminal complement components and sustains an anti-inflammatory innate immune response: implications for systemic autoimmunity. J. Exp. Med. 192, 1353–1364 (2001).

    Google Scholar 

  21. Savill, J. S., Hogg, N., Ren, Y. & Haslett, C. Thrombospondin co-operates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis. J. Clin. Invest. 90, 1513–1522 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ren, Y., Silverstein, R. L., Allen, J. & Savill, J. CD36 gene transfer confers capacity for phagocytosis of cells undergoing apoptosis. J. Exp. Med. 181, 1857–1862 (1995). This study was the first to show the principle of 'gain of phagocytic function'.

    CAS  PubMed  Google Scholar 

  23. Sambrano, G. R. & Steinberg, D. Recognition of oxidatively damaged and apoptotic cells by an oxidized low-density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine. Proc. Natl Acad. Sci. USA 92, 1396–1400 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chang, M. -K. et al. Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc. Natl Acad. Sci. USA 96, 6353–6358 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kagan, V. E. et al. A role for oxidative stress in apoptosis: oxidation and externalisation of phosphatidylserine is required for macrophage clearance of cells undergoing Fas-mediated apoptosis. J. Immunol. 169, 487–499 (2002).

    CAS  PubMed  Google Scholar 

  26. Shaw, P. X. et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance and protective immunity. J. Clin. Invest. 105, 1731–1740 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Oka, K. et al. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc. Natl Acad. Sci. USA 95, 9535–9540 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Platt, N., Suzuki, H., Kurihara, Y., Kodama, T. & Gordon, S. Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro. Proc. Natl Acad. Sci. USA 93, 12456–12460 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Platt, N., Suzuki, H., Kodama, T. & Gordon, S. Apoptotic thymocyte clearance in scavenger receptor class A-deficient mice is apparently normal. J. Immunol. 164, 4861–4867 (2000).

    CAS  PubMed  Google Scholar 

  30. Dini, L., Autori, F., Lentini, A., Olivierio, S. & Piacentini, M. The clearance of apoptotic cells in the liver is mediated by the asialoglycoprotein receptor. FEBS Lett. 296, 174–178 (1992).

    CAS  PubMed  Google Scholar 

  31. Duvall, E., Wyllie, A. H. & Morris, R. G. Macrophage recognition of cells undergoing programmed cell death. Immunology 56, 351–358 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Fadok, V. A., Bratton, D. L., Frasch, S. C., Warner, M. L. & Henson, P. M. The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ. 5, 557–563 (1998).

    Google Scholar 

  33. Fadok, V. A. et al. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal of macrophages. J. Immunol. 148, 2207–2216 (1992).

    CAS  PubMed  Google Scholar 

  34. Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000). References 33 and 34 describe the discovery of the first 'eat-me' flag on dying cells.

    CAS  PubMed  Google Scholar 

  35. Verhoven, B., Schlegel, R. A. & Williamson, P. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J. Exp. Med. 182, 1597–1601 (1995).

    CAS  PubMed  Google Scholar 

  36. Frasch, S. C. et al. Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase Cδ. J. Biol. Chem. 275, 23065–23073 (2000).

    CAS  PubMed  Google Scholar 

  37. Marguet, D., Luciani, M. F., Moynault, A., Williamson, P. & Chimini, G. Engulfment of apoptotic cells involves the redistribution of membrane phosphatidlyserine on phagocyte and prey. Nature Cell Biol. 1, 454–456 (1999).

    CAS  PubMed  Google Scholar 

  38. Balasubramanian, K., Chandra, J. & Schroit, A. J. Immune clearance of phosphatidylserine-expressing cells by phagocytes. The role of β2-glycoprotein I in macrophage recognition. J. Biol. Chem. 272, 31113–31117 (1997).

    CAS  PubMed  Google Scholar 

  39. Cocca, B. A. et al. Structural basis for autoantibody recognition of phosphatidylserine-β2 glycoprotein 1 and apoptotic cells. Proc. Natl Acad. Sci. 98, 13826–13831 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Moffatt, O. D., Devitt, A., Bell, E. D., Simmons, D. L. & Gregory, C. D. Macrophage recognition of ICAM-3 on apoptotic leukocytes. J. Immunol. 162, 6800–6810 (1999).

    CAS  PubMed  Google Scholar 

  41. Hughes, J., Liu, Y., Ren, Y. & Savill, J. Human glomerular mesangial cell phagocytosis of apoptotic cells is mediated by a CD36-independent vitronectin receptor/thrombospondin recognition mechanism. J. Immunol. 158, 4389–4397 (1997).

    CAS  PubMed  Google Scholar 

  42. Parnaik, R., Raff, M. C. & Scholes, J. Differences between the clearance of apoptotic cells by professional and non-professional phagocytes. Curr. Biol. 10, 857–860 (2000).

    CAS  PubMed  Google Scholar 

  43. Brown, S. et al. Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature (in the press). A new insight into discrimination between living and dying cells — apoptosis switches the function of an immunoglobulin-superfamily molecule so that detachment is disabled, which converts a repulsive interaction to an adhesive one.

  44. Knepper-Nicolai, B., Brown, S. B. & Savill, J. Constitutive apoptosis in human neutrophils requires synergy between calpains and the proteasome downstream of caspases. J. Biol. Chem. 273, 30530–30536 (1998).

    CAS  PubMed  Google Scholar 

  45. Chimini, G. Apoptosis: repulsive encounters. Nature 418, 139–142 (2002).

    CAS  PubMed  Google Scholar 

  46. Reddien, P. W., Cameron, S. & Horvitz, H. R. Phagocytosis promotes programmed cell death in C. elegans. Nature 412, 198–202 (2001).

    CAS  PubMed  Google Scholar 

  47. Hoeppner, D. J., Hentgartner, M. O. & Schnabel, R. Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature 412, 202–206 (2001).

    CAS  PubMed  Google Scholar 

  48. Brown, S. B. & Savill, J. Phagocytosis triggers macrophage release of Fas-ligand and induces apoptosis of bystander leucocytes. J. Immunol. 162, 480–485 (1999).

    CAS  PubMed  Google Scholar 

  49. Hanayama, R. et al. Identification of a factor that links apoptotic cells to phagocytes. Nature 417, 182–187 (2002).

    CAS  PubMed  Google Scholar 

  50. Hoffmann, P. R. et al. Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J. Cell Biol. 155, 649–660 (2001). A key study indicating that the phosphatidylserine receptor promotes ingestion of tethered apoptotic cells and fluid through macropinocytosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Meagher, L. C., Savill, J. S., Baker, A. & Haslett, C. Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2 . J. Leukocyte Biol. 52, 269–273 (1992). The original demonstration of neutral clearance of apoptotic cells without activating macrophages.

    CAS  PubMed  Google Scholar 

  52. Stern, M., Savill, J. & Haslett, C. Human monocyte-derived macrophage phagocytosis of senescent eosinophils undergoing apoptosis: mediation by αvβ3/CD36/thrombospondin recognition mechanism and lack of phlogistic response. Am. J. Pathol. 149, 911–921 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wright, S. D. & Silverstein, S. C. Receptors for C3b and C3bi promote phagocytosis but not the release of toxic oxygen from human phagocytes. J. Exp. Med. 158, 2016–2023 (1983).

    CAS  PubMed  Google Scholar 

  54. Marth, T. & Kelsall, B. L. Regulation of interleukin-12 by complement receptor 3 signalling. J. Exp. Med. 185, 1987–1995 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Voll, R. E., Herrmann, M., Roth, E. A., Stach, C. & Kalden, J. R. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997). The title of this paper highlights a key discovery in the field of apoptosis.

    CAS  PubMed  Google Scholar 

  56. Newman, S. L., Henson, J. E. & Henson, P. M. Phagocytosis of senescent neutrophils by human monocyte-derived macrophages and rabbit inflammatory macrophages. J. Exp. Med. 156, 430–442 (1982).

    CAS  PubMed  Google Scholar 

  57. Byrne, A. & Reen, D. J. Lipopolysaccharide induces rapid production of IL-10 by monocytes in the presence of apoptotic neutrophils. J. Immunol. 168, 1968–1997 (2002).

    CAS  PubMed  Google Scholar 

  58. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF. J. Clin. Invest. 101, 890–898 (1998). A classical paper defining a role for TGF-β1 in the anti-inflammatory clearance of dying cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. McDonald, P. P., Fadok, V. A., Bratton, D. & Henson, P. M. Transcriptional and translational regulation of inflammatory mediator production by endogenous TGF-β in macrophages that have ingested apoptotic cells. J. Immunol. 163, 6164–6172 (1999).

    CAS  PubMed  Google Scholar 

  60. Cocco, R. E. & Ucker, D. S. Distinct modes of macrophage recognition for apoptotic and necrotic cells are not specified exclusively by phosphatidylserine exposure. Mol. Biol. Cell 12, 919–930 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Huynh, M. -L. N., Fadok, V. A. & Henson, P. M. Phosphatidylserine-dependent ingestion of apoptotic cells promoted TGF-β1 secretion and the resolution of inflammation. J. Clin. Invest. 109, 41–50 (2002). The first in vivo demonstration that the clearance of apoptotic cells can suppress inflammatory responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Duffield, J. A. et al. Activated macrophages direct apoptosis and suppress mitosis of mesangial cells. J. Immunol. 164, 2110–2119 (2000).

    CAS  PubMed  Google Scholar 

  63. Reiter, I., Krammer, B. & Schwamberger, G. Differential effect of apoptotic versus necrotic tumor cells on macrophage antitumor activities. J. Immunol. 163, 1730–1732 (1999).

    CAS  PubMed  Google Scholar 

  64. Duffield, J. S., Ware, C. F., Ryffel, B. & Savill, J. Suppression by apoptotic cells defines tumour necrosis factor-mediated induction of glomerular mesangial cell apoptosis by activated macrophages. Am. J. Pathol. 159, 1397–1404 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Freire-de-Lima, C. G. et al. Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages. Nature 403, 199–203 (2000).

    CAS  PubMed  Google Scholar 

  66. Gao, Y., Herndon, J. M., Zhang, H., Griffith, T. S. & Ferguson, T. A. Anti-inflammatory effects of CD95 ligand (FasL)-induced apoptosis. J. Exp. Med. 188, 887–896 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen, W. -J., Frank, M. E., Jin, W. & Wahl, S. M. TGF-β released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14, 715–725 (2001).

    CAS  PubMed  Google Scholar 

  68. Lorimore, S. A., Coates, P. J., Scobie, G. E., Milne, G. & Wright, E. G. Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? Oncogene 20, 7085–7095 (2001).

    CAS  PubMed  Google Scholar 

  69. Kurosaka, K., Watanabe, N. & Kobayashi, Y. Production of proinflammatory cytokines by phorbol myristate acetate-treated THP-1 cells and monocyte-derived macrophages after phagocytosis of apoptotic CTLL-2 cells. J. Immunol. 161, 6245–6249 (1998).

    CAS  PubMed  Google Scholar 

  70. Basu, S., Binder, R. J., Ramalingam, T. & Srivastava, P. K. CD91 is a common receptor for heat-shock proteins pg96, hsp70 and calreticulin. Immunity 14, 303–313 (2001).

    CAS  PubMed  Google Scholar 

  71. Miwa, K. et al. Caspase-1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas ligand. Nature Med. 4, 1287–1292 (1998).

    CAS  PubMed  Google Scholar 

  72. Sansonetti, P. J. et al. Caspase-1 activation of IL-1β and IL-8 are essential for Shigella flexneri-induced inflammation. Immunity 12, 581–590 (2000).

    CAS  PubMed  Google Scholar 

  73. Restifo, N. P. Building better vaccines: how apoptotic cell death can induce inflammation and activate innate and adaptive immunity. Curr. Opin. Immunol. 12, 597–603 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Horino, K. et al. A monocyte chemotactic factor S19 ribosomal protein dimer in phagocytic clearance of apoptotic cells. Lab. Invest. 78, 603–617 (1998).

    CAS  PubMed  Google Scholar 

  75. Rubartelli, A., Foggi, A. & Zocchi, M. K. The selective engulfment of apoptotic bodies by dendritic cells is mediated by the αvβ3 integrin and requires intracellular and extracellular calcium. Eur. J. Immunol. 27, 1893–1900 (1997). The first report of phagocytosis of apoptotic cells by dendritic cells.

    CAS  PubMed  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Urban, B. C., Willcox, N. & Roberts, D. J. A role for CD36 in the regulation of dendritic-cell function. Proc. Natl Acad. Sci. USA 98, 8750–8755 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Stuart, L. M. et al. Inhibitory effects of apoptotic-cell ingestion upon endotoxin-driven myeloid dendritic-cell maturation. J. Immunol. 168, 1627–1635 (2002). References 77 and 78 show the suppressive effects of apoptotic-cell ingestion on immature dendritic cells, which might contribute to cross-tolerization (see also reference 94).

    CAS  PubMed  Google Scholar 

  79. Urban, B. C. et al. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400, 73–77 (1999).

    CAS  PubMed  Google Scholar 

  80. Bellone, M. et al. Processing of engulfed apoptotic bodies yields T-cell epitopes. J. Immunol. 159, 5391–5399 (1997). The first demonstration that the phagocytosis of apoptotic cells might promote the presentation of antigen to primed T cells.

    CAS  PubMed  Google Scholar 

  81. 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. Nature Cell Biol. 1, 362–368 (1999).

    CAS  PubMed  Google Scholar 

  82. Schulz, O., Pennington, D. J., Hodivala-Dilke, K., Febbraio, M. & Reis e Sousa, C. CD36 or αvβ3 and αvβ5 integrins are not essential for MHC class I cross-presentation of cell-associated antigen by CD8α+ murine dendritic cells. J. Immunol. 168, 6057–6065 (2002).

    CAS  PubMed  Google Scholar 

  83. Belz, G. T. et al. CD36 is differentially expressed by CD8+ splenic dendritic cells but is not required for cross-presentation in vivo. J. Immunol. 168, 6066–6070 (2002).

    CAS  PubMed  Google Scholar 

  84. Inaba, K. et al. Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells. J. Exp. Med. 188, 2163–2169 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Casciola-Rosen, L. A., Annhalt, G. J. & Rosen, A. DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis. J. Exp. Med. 182, 1625–1634 (1995).

    CAS  PubMed  Google Scholar 

  86. Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nature Med. 5, 1249–1255 (1999).

    CAS  PubMed  Google Scholar 

  87. Sauter, B. B. et al. 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. 191, 423–433 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Basu, S., Binder, R. J., Suto, R., Anderson, K. M. & Srivastava, P. K. Necrotic but not apoptotic cell death releases heat-shock proteins which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway. Int. Immunol. 12, 1539–1546 (2000).

    CAS  PubMed  Google Scholar 

  89. Fadok, V. A., Bratton, D. L., Guthrie, L. & Henson, P. M. Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases. J. Immunol. 166, 6847–6854 (2001).

    CAS  PubMed  Google Scholar 

  90. Rovere, P. et al. Bystander apoptosis triggers dendritic-cell maturation and antigen-presenting function. J. Immunol. 161, 4467–4471 (1998).

    CAS  PubMed  Google Scholar 

  91. Steinman, R. M., Turley, S., Mellman, I. & Inaba, K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191, 411–416 (2000). A fundamental position statement in the field.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Huang, F. -P. et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T-cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435–443 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Nakamura, K. et al. Unresponsiveness of peripheral T cells induced by apoptotic bodies derived from autologous T cells. Cell. Immunol. 193, 147–154 (1999).

    CAS  PubMed  Google Scholar 

  94. Albert, M. L., Jegathesan, M. & Darnell, R. B. Dendritic cells acquire antigen from apoptotic cells and cross-tolerize antigen-specific CD8+ T cells. Nature Immunol. 2, 1010–1017 (2001). A crucial piece in the puzzle of how dendritic-cell handling of apoptotic cells might regulate immune responses.

    CAS  Google Scholar 

  95. 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).

    CAS  PubMed  Google Scholar 

  96. Magnus, T., Chan, A., Grauer, O., Toyka, T. V. & Gold, R. Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation. J. Immunol. 167, 5004–5010 (2001).

    CAS  PubMed  Google Scholar 

  97. Mevorach, D., Zhou, J. L., Song, X. & Elkon, K. B. Systemic exposure to irradiated apoptotic cells induces autoantibody production. J. Exp. Med. 188, 387–392 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Licht, R., Jacobs, C. W. M., Tax, W. J. M. & Berden, J. H. M. No constitutive defect in phagocytosis of apoptotic cells by resident peritoneal macrophages from pre-morbid lupus mice. Lupus 10, 102–107 (2001).

    CAS  PubMed  Google Scholar 

  99. Herrmann, M. et al. Impaired phagocytosis of apoptotic-cell material by monocyte-derived macrophages from patients with systemic lupus erythematosus. Arthritis Rheum. 41, 1241–1250 (1998).

    CAS  PubMed  Google Scholar 

  100. Napirei, M. et al. Features of systemic lupus erythematosus in DNase1-deficient mice. Nature Genet. 25, 177–181 (2000).

    CAS  PubMed  Google Scholar 

  101. Bickerstaff, M. C. et al. Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity. Nature Med. 5, 694–697 (1999).

    CAS  PubMed  Google Scholar 

  102. Familian, A. et al. Chromatin-independent binding of serum amyloid P component to apoptotic cells. J. Immunol. 167, 647–654 (2001).

    CAS  PubMed  Google Scholar 

  103. Botto, M. et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nature Genet. 19, 56–59 (1998).

    CAS  PubMed  Google Scholar 

  104. Lu, Q. & Lemke, G. Homeostatic regulation of the immune system by receptor tyrosine kinases of the Tyro-3 family. Science 293, 306–311 (2001).

    CAS  PubMed  Google Scholar 

  105. Wilkinson, R. et al. Platelet endothelial-cell adhesion molecule-1 (PECAM-1/CD31) acts as a regulator of B-cell development, B-cell antigen receptor (BCR)-mediated activation and autoimmune disease. Blood 100, 184–193 (2002).

    CAS  PubMed  Google Scholar 

  106. Price, B. E. et al. Anti-phospholipid autoantibodies bind to apoptotic, but not viable, thymocytes in a β2-glycoprotein I-independent manner. J. Immunol. 157, 2201–2208 (1996).

    CAS  PubMed  Google Scholar 

  107. Manfredi, A. A. et al. Apoptotic-cell clearance in systemic lupus erythematosus. I. Opsonization by antiphospholipid antibodies. Arthritis Rheum. 41, 205–214 ( 1998).

    CAS  PubMed  Google Scholar 

  108. Miranda-Carus, M. -E. et al. Anti-SSA/Ro and anti-SSB/La autoantibodies bind the surface of apoptotic fetal cardiocytes and promote secretion of TNF-α by macrophages. J. Immunol. 165, 5345–5351 (2000).

    CAS  PubMed  Google Scholar 

  109. Cocca, B. A., Cline, A. M. & Radic, M. Z. Blebs and apoptotic bodies are B-cell autoantigens. J. Immunol. 169, 159–166 (2002).

    CAS  PubMed  Google Scholar 

  110. Rovere, P. et al. Dendritic-cell presentation of antigens from apoptotic cells in a proinflammatory context: role of opsonizing anti-β2-glycoprotein I antibodies. Arthritis Rheum. 42, 1412–1420 (1999).

    CAS  PubMed  Google Scholar 

  111. Harper, L., Ren, Y., Savill, J., Adu, D. & Savage, C. Antineutrophil cytoplasmic antibodies induce reactive oxygen-dependent dysregulation of primed neutrophil apoptosis and clearance by macrophages. Am. J. Pathol. 157, 211–220 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Reddien, P. W. & Horvitz, H. R. CED-2/Crkll and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nature Cell Biol. 2, 131–135 (2000).

    CAS  PubMed  Google Scholar 

  113. Wu, Y. C. & Horvitz, H. R. C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature 392, 501–504 (1998).

    CAS  PubMed  Google Scholar 

  114. Albert, M. L., Kim, J. -I. & Birge, R. B. The αvβ5 integrin recruits the CrkII/Dock180/Rac1 molecular complex for phagocytosis of apoptotic cells. Nature Cell Biol. 2, 899–905 (2000).

    CAS  PubMed  Google Scholar 

  115. Leverrier, Y. & Ridley, A. J. Requirement for Rho GTPases and PI3-kinases during apoptotic-cell phagocytosis by macrophages. Curr. Biol. 11, 195–199 (2000).

    Google Scholar 

  116. Tosello-Trampont, A. -C., Brugnera, E. & Ravichandran, K. S. Evidence for a conserved role for CrkII and Rac in engulfment of apoptotic cells. J. Biol. Chem. 276, 13797–13802 (2000).

    Google Scholar 

  117. Leverrier, Y. et al. Cutting edge: the Wiskott-Aldrich syndrome protein is required for efficient phagocytosis of apoptotic cells. J. Immunol. 166, 4831–4834 (2001).

    CAS  PubMed  Google Scholar 

  118. Caron, E. & Hall, A. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282, 1717–1721 (1998).

    CAS  PubMed  Google Scholar 

  119. Hart, S. P., Dougherty, G. J., Haslett, C. & Dransfield, I. CD44 regulates phagocytosis of apoptotic neutrophil granulocytes, but not apoptotic lymphocytes, by human macrophages. J. Immunol. 159, 919–925 (1997).

    CAS  PubMed  Google Scholar 

  120. Meagher, L. C., Cousin, J. M., Seckl, J. R. & Haslett, C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J. Immunol. 156, 4422–4428 (1996).

    CAS  PubMed  Google Scholar 

  121. Liu, Y. et al. Glucocorticoids promote non-phlogistic phagocytosis of apoptotic leukocytes. J. Immunol. 162, 3639–3646 (1999).

    CAS  PubMed  Google Scholar 

  122. Giles, K. M. et al. Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation and high levels of active Rac. J. Immunol. 167, 976–986 (2001).

    CAS  PubMed  Google Scholar 

  123. Godson, C. et al. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, 1663–1667 (2000).

    CAS  PubMed  Google Scholar 

  124. McMahon, B., Mitchell, S., Brady, H. R. & Godson, C. Lipoxins: revelations on resolution. Trends Pharmacol. Sci. 22, 391–395 (2001).

    CAS  PubMed  Google Scholar 

  125. Mitchell, S. et al. Lipoxins stimulate macrophage phagocytosis of apoptotic neutrophils in acute inflammation in vivo. J. Am. Soc. Nephrol. (in the press).

Download references

Acknowledgements

We have received long-term support from the Wellcome Trust and the Medical Research Council. Many colleagues have been instrumental in developing the ideas that are presented here, not least those whose work could not be cited owing to space constraints. C. Gilchrist typed the manuscript.

Author information

Authors and Affiliations

  1. Departments of Clinical & Surgical Sciences (Internal Medicine) and Medical & Radiological Sciences (Respiratory Medicine), MRC/University of Edinburgh Centre for Inflammation Research, Royal Infirmary, Lauriston Place, Edinburgh, EH3 9YW, UK

    John Savill, Ian Dransfield, Chris Gregory & Chris Haslett

Authors
  1. John Savill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ian Dransfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chris Gregory
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chris Haslett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John Savill.

Related links

Related links

DATABASES

LocusLink

αVβ3 integrin

ABC1

ARP2/3 complex

Axl

β2-GPI

β2-integrin

C1q

C4

calreticulin

caspase-1

CD11B

CD11C

CD14

CD18

CD31

CD36

CD44

CD68

CD86

CD91

CD95

CD95L

CDC42

CR3

CR4

CRKII

CRP

DNase I

DOCK180

Gas6

GM-CSF

ICAM3

IFN-γ

IL-1β

IL-8

IL-10

IL-12

IL-18

LOX1

MBL

Mer

MFGE8

myeloperoxidase

p130CAS

paxillin

proteinase-3

PtdSerR

PYK2

RAC1

RHOA

S19

SAP

SRA

TGF-β1

TNF

TSP1

Tyro3

WASp

OMIM

SLE

WAS

Rights and permissions

Reprints and permissions

About this article

Cite this article

Savill, J., Dransfield, I., Gregory, C. et al. A blast from the past: clearance of apoptotic cells regulates immune responses. Nat Rev Immunol 2, 965–975 (2002). https://doi.org/10.1038/nri957

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri957

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing