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Dying cells actively regulate adaptive immune responses

Key Points

  • 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.

Abstract

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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Figure 1: A timeline of the history of discoveries and concepts in the study of cell death and cross-priming.
Figure 2: Cell death pathways are upstream drivers of adaptive immunity.
Figure 3: The ripoptosome integrates cell stress, innate immune and cell death signalling pathways.
Figure 4: Immunological classification of cell death.

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Acknowledgements

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.

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Glossary

Antigens

Substances or molecules that are capable of binding to an antibody or a T cell receptor.

Cross-priming

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.

Cross-presentation

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.

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.

Necrosis

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.

Immunogen

A substance or a molecule that has the ability to induce an adaptive immune response.

Apoptosis

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.

Necroptosis

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.

Pyroptosis

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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