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  • Review Article
  • Published:

Immunogenic and tolerogenic cell death

Nature Reviews Immunology volume 9, pages 353–363 (2009)Cite this article

Key Points

  • As cells are infected by microorganisms, they can pre-emptively die to prevent the replication and spreading of the pathogen. Cell death that is associated with the presence of pathogen-associated molecular patterns (PAMPs) can stimulate vigorous immune responses.

  • In the absence of PAMPs, damage-associated molecular patterns (DAMPs) produced by dying cells can stimulate an immune response that can elicit the specific recognition of antigens expressed by dying cells (for example, tumour antigens).

  • The nature of the immune response to cell death depends on which cells die, where they die, how they die, which cell engulfs them and when (or if) an associated antigen has been or will be recognized. Variations in these factors can have consequences that range from effective anti-pathogen or antitumour responses to autoimmune pathology.

  • The simple idea that apoptosis is tolerogenic or non-immunogenic and that necrosis is immunogenic is an oversimplification. Thus, apoptosis of tumour cells that is induced by chemotherapy can prime an efficient immune response, which in turn can contribute to the efficacy of antitumour regimens.

  • Various DAMPs contribute to the immunogenicity of apoptotic cell death. These include the surface exposure of chaperone proteins (such as calreticulin) or the release of proteins, such as high-mobility group box 1 protein (HMGB1) and SIN3A-associated protein 130 (SAP130) among others. The catabolic action of caspases and autophagy can also contribute to the immunogenicity of cell death.

  • The tolerogenic effect of cell death depends on many factors, including the absence of T cell help, the location of the dying cells (which in part dictates their engulfment by distinct dendritic cell (DC) subtypes), the maturation state of the DC, the production of immunosuppressive factors (such as transforming growth factor-β) or the modification of DAMPs (for example, oxidation of HMGB1 that results in its inactivation).

  • In conclusion, the mechanisms that determine the immune response to dead and dying cells are complex. Understanding (and possibly manipulating) these mechanisms can have important implications for cancer biology, infectious disease, tissue injury and autoimmunity.

Abstract

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

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Figure 1: Some characteristics of immunogenic cell death.
Figure 2: Suggested mechanisms of tolerance induction by apoptotic cells.

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Acknowledgements

L.Z. and G.K. are supported by grants from the Ligue Nationale contre le Cancer, the European Union (ALLOSTEM, DC-THERA for L.Z.; Active p53, ApoSys, ApopTrain, RIGHT for G.K.), Fondation pour la Recherche Médicale, Cancéropôle Ile-de-France, Institut National du Cancer and Agence Nationale pour la Recherche. T.A.F. is supported by National Institutes of Health (NIH) grants EY06765, EY15570, and the Department of Ophthalmology and Visual Sciences core grant (EY02687). Support was also received from the Foundation for Fighting Blindness (Owings Mills, Maryland, USA), Research to Prevent Blindness (New York, USA), and the Macular Vision Research Foundation (West Conshohocken, Pennsylvania, USA). D.R.G. is supported by grants from the NIH and by the American Lebanese and Syrian Associated Charities.

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Author notes

  1. Faculté Paris Sud-Université, Paris 11, F-94805 Kremlin-Bicêtre, France.

Authors and Affiliations

  1. Department of Immunology, St Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Douglas R. Green

  2. Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Thomas Ferguson

  3. Institut National de la Santé et de la Recherche Médicale, Villejuif, U805, F-94805, France

    Laurence Zitvogel

  4. Center of Clinical Investigation BT507, Villejuif, F-94805, France

    Laurence Zitvogel

  5. Institut Gustave Roussy, Villejuif, F94805, France

    Laurence Zitvogel & Guido Kroemer

  6. Institut National de la Santé et de la Recherche Médicale, U848, Villejuif, F-94805, France

    Guido Kroemer

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  1. Douglas R. Green
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  2. Thomas Ferguson
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  3. Laurence Zitvogel
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  4. Guido Kroemer
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Glossary

Damage-associated molecular pattern

(DAMP). A molecule that is released from the degraded stroma (for example, hyaluronate), nucleus (for example, high-mobility group box 1 protein) and the cytoplasm (for example, ATP, uric acid, S100 calcium-binding proteins and heat shock proteins) as a result of cellular stress, cellular damage and non-physiological cell death. DAMPs are thought to elicit local inflammatory reactions.

Dendritic cell

The main antigen-presenting cell of the immune system. Engulfment of dying cells by dendritic cells can lead to tolerance or immune responses to associated antigens.

Delayed-type hypersensitivity

A cellular immune response to antigen that develops over 24 – 72 hours, is associated with the infiltration of T cells and monocytes and is dependent on the production of T helper 1-type cytokines.

Tolerance

A term that denotes lymphocyte non-responsiveness to antigen, but implies an active process, not simply a passive lack of response.

Hapten

A molecule that can bind antibody but cannot by itself elicit an immune response. Antibodies that are specific for a hapten can be generated when the hapten is chemically linked to a protein carrier that can elicit a T cell response.

Contact hypersensitivity

A form of delayed-type hypersensitivity (type IV), in which T cells respond to antigens that are introduced through skin contact. This step requires dendritic cell mobilization from the skin to the draining lymph nodes to prime the antigen-specific T cells.

CD95L

An apoptosis-inducing or death ligand of the tumour necrosis factor family.

Caspase

An enzyme belonging to a family of cytoplasmic proteases that cleave their substrate after an aspartic acid residue. Initiator caspases are typically activated in response to particular stimuli. Effector caspases are activated by initiator caspases and are particularly important for the ordered dismantling of vital cellular structures.

Cross-present

The presentation of exogenous antigen to CD8+ T cells by antigen-presenting cells (APCs). The antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation, resulting in the initiation of a CD8+ T cell response to an antigen that is not present within APCs.

Activation-induced cell death

(AICD). The apoptotic cell death of activated lymphocytes. It ensures the rapid elimination of effector cells after their antigen-dependent clonal expansion. Defects in AICD result in lymphoproliferative diseases that are associated with autoimmune disorders.

NKG2D

A lectin-type activating receptor that is expressed on the surface of natural killer (NK), NKT, γδ T cells and some cytolytic CD8+ αβ T cells. NKG2D recognizes the ligands MHC class I-polypeptide-related sequence A (MICA) and MICB in humans and retinoic acid early transcript 1 (RAE1) and H60 in mice. Such ligands are generally expressed by infected, stressed or transformed cells.

Senescence

A nearly irreversible stage of permanent G1 cell cycle arrest, linked to morphological changes (flattening of the cells), metabolic changes and changes in gene expression, the induction of which depends on p53 and cell cycle blockers such as p21 and p16.

p53

An important transcription factor that is activated by numerous genotoxic insults to induce cell cycle arrest, cell senescence or apoptosis. p53 is frequently mutated or functionally inactivated in cancer.

Inflammasome

A molecular complex of several proteins that on assembly cleaves pro-interleukin-1 (IL-1), thereby producing active IL-1.

HMGB1

A DAMP that is released from dying cells. It can be modified by reactive oxygen species to alter its immunostimulatory effects.

Macroautophagy

The largely non-specific autophagic sequestration of cytoplasm into a double- or multiple-membrane-delimited compartment (an autophagosome) of non-lysosomal origin. Certain proteins, organelles and pathogens may be selectively degraded by macroautophagy.

Immune-privileged site

An area in the body that has a decreased but not absent immune response to foreign antigens, including tissue grafts. These sites include the brain, eye, testis and placenta.

'Helpless' CTL

A CD8+ T cell that has undergone activation without additional stimulation ('help') by CD4+ T cells.

Reactive oxygen species

Oxygen radicals that are produced by the mitochondrial respiratory chain and by other processes. When found in excessive quantities, they can cause intracellular and mitochondrial damage, which promotes cell death.

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Green, D., Ferguson, T., Zitvogel, L. et al. Immunogenic and tolerogenic cell death. Nat Rev Immunol 9, 353–363 (2009). https://doi.org/10.1038/nri2545

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