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The danger theory of immunity revisited

Nature Reviews Immunology volume 24, pages 912–928 (2024)Cite this article

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Abstract

The danger theory of immunity, introduced by Polly Matzinger in 1994, posits that tissue stress, damage or infection has a decisive role in determining immune responses. Since then, a growing body of evidence has supported the idea that the capacity to elicit cognate immune responses (immunogenicity) relies on the combination of antigenicity (the ability to be recognized by T cell receptors or antibodies) and adjuvanticity (additional signals arising owing to tissue damage). Here, we discuss the molecular foundations of the danger theory while focusing on immunologically relevant damage-associated molecular patterns, microorganism-associated molecular patterns, and neuroendocrine stress-associated immunomodulatory molecules, as well as on their receptors. We critically evaluate patient-relevant evidence, examining how cancer cells and pathogenic viruses suppress damage-associated molecular patterns to evade immune recognition, how intestinal dysbiosis can reduce immunostimulatory microorganism-associated molecular patterns and compromise immune responses, and which hereditary immune defects support the validity of the danger theory. Furthermore, we incorporate the danger hypothesis into a close-to-fail-safe hierarchy of immunological tolerance mechanisms that also involve the clonal deletion and inactivation of immune cells.

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Fig. 1: The danger theory of immunity in a nutshell.
Fig. 2: Immune responses elicited in sterile tissues.
Fig. 3: Clinically validated pathways leading to immune escape of cancer cells and human viruses.
Fig. 4: Danger signals modulating the antimicrobial immune response.
Fig. 5: Revisiting the danger theory of immunity.

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Acknowledgements

O.K. receives funding from Institut National du Cancer (INCa) and Association pour la recherche sur le cancer (ARC). G.K. and L.Z. are supported by the Ligue contre le Cancer (équipe labellisée); ARC; Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; European Union Horizon 2020 research and innovation programmes Oncobiome (grant agreement number: 825410, project acronym: ONCOBIOME, project title: Gut OncoMicrobiome Signatures (GOMS) associated with cancer incidence, prognosis and prediction of treatment response), Prevalung (grant agreement number 101095604, project acronym: PREVALUNG EU, project title: Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception), INCa; LabEx Immuno-Oncology ANR-18-IDEX-0001; and the RHUs Immunolife and LUCA-pi (ANR-21-RHUS-0017 and ANR-23-RHUS-0010, both dedicated to France Relance 2030). G.K. is supported by Agence National de la Recherche (ANR-22-CE14-0066 VIVORUSH, ANR-23-CE44-0030 COPPERMAC and ANR-23-R4HC-0006 Ener-LIGHT); European Joint Programme on Rare Diseases (EJPRD) Wilsonmed; European Research Council Advanced Investigator Award (ERC-2021-ADG, grant number: 101052444, project acronym: ICD-Cancer, project title: Immunogenic cell death (ICD) in the cancer-immune dialogue); The ERA4 Health Cardinoff Grant Ener-LIGHT; European Union Horizon 2020 research and innovation programmes Neutrocure (grant agreement number: 861878, project acronym: Neutrocure, project title: Development of ‘smart’ amplifiers of reactive oxygen species specific to aberrant polymorphonuclear neutrophils for treatment of inflammatory and autoimmune diseases, cancer and myeloablation); national support managed by the Agence Nationale de la Recherche under the France 2030 programme (reference number: 21-ESRE-0028, ESR/Equipex + Onco-Pheno-Screen); Hevolution Network on Senescence in Aging (reference HF-E Einstein Network); Institut Universitaire de France; a Cancer Research ASPIRE Award from the Mark Foundation; PAIR-Obésité INCa_1873, Seerave Foundation; SIRIC Cancer Research and Personalized Medicine (CARPEM, SIRIC CARPEM INCa-DGOS-Inserm-ITMO Cancer_18006 supported by Institut National du Cancer, Ministère des Solidarités et de la Santé and INSERM). Views and opinions expressed are those of the author(s) only and do not necessarily reflect those of the European Union, the European Research Council or any other granting authority. None of the granting authorities can be held responsible for them.

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Authors and Affiliations

  1. Centre de Recherche des Cordeliers, INSERM U1138, Équipe Labellisée — Ligue Nationale contre le Cancer, Université Paris Cité, Sorbonne Université, Paris, France

    Guido Kroemer, Léa Montégut & Oliver Kepp

  2. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France

    Guido Kroemer, Léa Montégut & Oliver Kepp

  3. Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

  4. Gustave Roussy Cancer Campus, Clinicobiome, Villejuif, France

    Laurence Zitvogel

  5. INSERM UMR 1015, ClinicObiome, Equipe Labellisée-Ligue Nationale contre le Cancer, Villejuif, France

    Laurence Zitvogel

  6. Université Paris-Saclay, Ile-de-France, Paris, France

    Laurence Zitvogel

  7. Center of Clinical Investigations in Biotherapies of Cancer (BIOTHERIS), Villejuif, France

    Laurence Zitvogel

Authors
  1. Guido Kroemer
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  2. Léa Montégut
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  3. Oliver Kepp
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  4. Laurence Zitvogel
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All authors researched data for the article. All authors contributed substantially to discussion of the content. G.K. wrote the article. All authors reviewed and edited the manuscript before submission.

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Correspondence to Guido Kroemer or Laurence Zitvogel.

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O.K. is a scientific co-founder of Samsara Therapeutics. O.K. has been working on research projects with Air Liquide, Daiichi Sankyo, Kaleido, Lytix Pharma, PharmaMar, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage. G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys and Vascage. G.K. is on the Board of Directors of the Bristol Myers Squibb Foundation France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. G.K. is in the scientific advisory boards of Hevolution, Institut Servier, Longevity Vision Funds and Rejuveron Life Sciences. G.K. is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic fibrosis and metabolic disorders. G.K.’s brother, R. Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. L.M. is a consultant of everImmune. L.Z. has held research contracts with GlaxoSmithKline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the Board of Directors of Transgene, is a cofounder of everImmune and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. The funders had no role in the design of the study; in the writing of the manuscript; or in the decision to publish the results.

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Glossary

Adjuvanticity

The ability of an agent to enhance the immune response by an adjuvant effect.

Antigenicity

The capacity of a molecule (often a protein or its peptides) to be bound by immunoglobulins or T cell receptors.

Apoptosis

A cell death modality in which plasma membrane integrity is conserved until the end of process, when caspase-3-dependent blebbing of the cells facilitates their final disintegration.

Beclin 1 complex

A polyprotein complex involved in the initiation of autophagy through the activation of a phosphatidylinositol 3-kinase.

Bile acids

Steroids that are produced by hepatocytes as primary bile acids to be secreted via bile into the duodenum. In the colon, bacteria metabolize primary bile acids so secondary bile acids that can be taken up and reach the liver to be modified to tertiary bile acids.

Calreticulin

(CALR). The most abundant luminal endoplasmic reticulum protein that can translocate to the cell surface in the context of immunogenic cell death.

Chemoembolization

Intra-arterial injection of chemotherapeutic substances together with particles that interrupt capillary blood flow.

Danger signals

The compendium of signals produced by damaged tissues that shapes the local inflammatory and immune responses.

Dysbiosis

An imbalance in the microbial composition that shifts from a normal, diverse gut flora to a dysfunctional array of microorganisms that compromises organismal health.

Enteropathies

Pathologies affecting the gut that can be diagnosed by histopathological examination revealing alterations of the mucosa and submucosal structures.

F-actin

Polymers of actin protein that form filamentous actin within microfilaments of the cytoskeleton.

Ferroptosis

Caspase-independent death caused by excessive peroxidation of cellular membranes.

Gut permeability

Failure to control the translocation of molecules and supramolecular entities (outer membrane vesicle and entire microorganisms) from inside the gastrointestinal tract through the cells lining the gut wall into the rest of the body.

Immune evasion

During tumour progression, cancer cells must escape from, or suppress, immunosurveillance to strive in an unrestrained fashion.

Immunogenic cell death

(ICD). A form of cell death that leads to the recognition of dead-cell antigens by T lymphocytes.

Immunogenicity

The capacity of an entity to induce an immune response based on the combination of antigenicity and adjuvanticity.

Integrated stress response

(ISR). A phylogenetically ancient stress response in which specific kinases phosphorylate eIF2α, causing a change from 5′ cap-dependent to 5′ cap-independent translation of mRNAs, hence shifting the range of mRNA species that are translated into proteins. ISR is required for calreticulin exposure as well as for autophagy enhancement.

Interferon-stimulated genes

(ISGs). A series of genes expressed after the action of type I interferons on their common receptors. Such genes encode antiviral and bactericidal proteins, pattern-recognition receptors, and chemokines and their receptors, as well as other immunostimulatory proteins.

Listeriolysin

A pore-forming toxin produced by Listeria monocytogenes.

Microbiota

The ecosystem formed by archae, bacteria, fungi, phages, protists, viruses and other microorganisms that colonizes the body.

Necroptosis

Caspase-independent death involving characteristic effector molecules such as RIPK3 and MLKL.

Neoadjuvant

Neoadjuvant therapies are administered before surgical removal of the tumour, whereas adjuvant therapies are administered after surgery.

Oncolytic viruses

Viruses that have been designed for the destruction of cancer cells.

Penumbra

Partially surviving tissue at the margin of the necrotic area.

Photodynamic therapy

A phototherapy involving intense light and a photosensitizing chemical agent.

Polarity

Initial classification led to the distinction of immunocytes in two classes (such as T helper cells: TH1 and TH2; and macrophages: M1 and M2). This dichotomy turned out to be an oversimplification owing to the existence of more than two classes and overlaps (multifunctionality).

Premortem stress

Activation of cellular stress pathways before cell death, defined by the irreversible permeabilization of the plasma membrane, occurs.

Pyroptosis

A type of cell death involving the activation of caspase-1 activation complexes that facilitates the maturation of IL-1β and the proteolytic activation of gasdermin D that then forms pores in the plasma membrane to release IL-1β.

Senescence

A state of close-to-irreversible cell cycle arrest linked to reduction of cellular functions, morphological changes and transcriptional reprogramming.

Senescence-associated secretory phenotype

Senescence is coupled to the secretion of a heterogeneous panel of cytokines, which may include IL6 and IL8, as well as transforming growth factor-β, but depends on the cell type and the upstream triggers.

Sepsis

The spread of infectious pathogens and their products to the bloodstream acutely causing a life-threatening systemic inflammatory response.

Serial passage

A method of growing bacteria or virus in iterations, usually in cell cultures, allowing the accumulation of mutations that are compatible with replication but not necessary for pathogenicity, hence leading to the attenuation of virulence.

Sickness behaviour

A coordinated set of adaptive behavioural changes that develops in the context of infectious disease.

Type I interferons

(IFN-Is). α-interferon and β-interferon that share the property to act on a common receptor, IFNAR.

Vita-PAMPs

Pathogen-associated molecular patterns that signify microbial viability.

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Kroemer, G., Montégut, L., Kepp, O. et al. The danger theory of immunity revisited. Nat Rev Immunol 24, 912–928 (2024). https://doi.org/10.1038/s41577-024-01102-9

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