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Cross-presentation by dendritic cells

Key Points

  • Two main pathways have been described for cross-presentation: the cytosolic pathway, in which antigen processing occurs in the cytosol, and the vacuolar pathway, in which antigen processing occurs within endocytic compartments. For both pathways, the origin and the site of loading of MHC class I molecules are still incompletely understood.

  • Limited proteolysis in the endocytic compartments of dendritic cells (DCs) favours cross-presentation by preventing the destruction of internalized antigens.

  • In the cytosolic pathway, exogenous antigens are translocated from endosomal compartments into the cytosol for degradation by the proteasome. The molecular machinery involved remains poorly characterized, but several lines of evidence suggest a role for endoplasmic reticulum proteins that could be delivered to endosomes and phagosomes through a specific pathway in cross-presenting DCs.

  • There are several subpopulations of mouse DCs, of which only some can efficiently cross-present antigens, probably owing to specific features of their endocytic compartments that favour cross-presentation through the cytosolic pathway. Whether some of the human DC subsets are also specialized at cross-presentation remains unclear.

  • During infections, cross-presentation is essential for the initiation of cytotoxic CD8+ T cell responses when DCs are not directly infected. The DC subsets involved differ depending on the site of infection and the inflammatory environment.

  • Cross-presentation of thymic epithelial cell-associated antigens by thymic DCs is involved in the deletion of autoreactive CD8+ T cells. In the periphery, cross-presentation of self antigens by DCs is also important for the maintenance of tolerance.

  • The manipulation of cross-presentation and in vivo targeting of cross-presenting DCs for the delivery of vaccines have proved promising strategies in mice, but a better understanding of human DC subsets is needed for translation to the clinic.

Abstract

The presentation of exogenous antigens on MHC class I molecules, known as cross-presentation, is essential for the initiation of CD8+ T cell responses. In vivo, cross-presentation is mainly carried out by specific dendritic cell (DC) subsets through an adaptation of their endocytic and phagocytic pathways. Here, we summarize recent advances in our understanding of the intracellular mechanisms of cross-presentation and discuss its role in immunity and tolerance in the context of specialization between DC subsets. Finally, we review current strategies to use cross-presentation for immunotherapy.

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Figure 1: Intracellular pathways for cross-presentation in dendritic cells.

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Acknowledgements

We thank members of the Amigorena laboratory for discussions. O.P.J. is a fellow of INSERM (Institut National de la Santé et de la Recherche Médicale). E.S. is a fellow of the Association pour la Recherche sur le Cancer. Our work is supported by INSERM, Institut Curie, the European Research Council (2008 Advanced Grant 233062 PhagoDC), la Ligue Nationale Contre le Cancer (LNCC) and l'Agence Nationale de la Recherche.

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Glossary

MHC class I-loading complex

A series of endoplasmic reticulum chaperone proteins that stabilize empty MHC class I molecules and control the loading of high-affinity peptides onto MHC class I molecules.

V-ATPase

(Vacuolar ATPase). A transmembrane protein complex that transports H+ ions across intracellular membranes in an ATP-dependent manner.

SNARE

(Soluble NSF attachment protein receptor). A member of a class of proteins that are required for membrane fusion events that occur in the course of vesicle trafficking and secretion.

Fluorescence resonance energy transfer

(FRET). A technique that is used to measure protein–protein interactions either by microscopy or by flow cytometry. Proteins fused to cyan, yellow or red fluorescent proteins are expressed and assessed for interaction by measuring the energy transfer between fluorophores. Such transfer can occur only if the proteins physically interact.

ERAD

(Endoplasmic reticulum-associated protein degradation). A pathway that targets proteins that are misfolded in the ER to the proteasome for degradation.

Pattern-recognition receptors

(PRRs). Host receptors (such as Toll-like receptors and NOD-like receptors) that can sense pathogen-associated molecular patterns. The term PRR is usually restricted to molecules that signal to modify gene expression programmes, leading to the expression and/or secretion of immune modulators (such as pro-inflammatory cytokines) that coordinate innate and adaptive immune responses. PRRs can be localized at the plasma membrane, in endosomal compartments or in the cytosol.

Trogocytosis

The transfer of plasma membrane fragments from one cell to another.

Anergy

A state of non-responsiveness to antigen. Anergic B cells or T cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Central tolerance

Central tolerance encompasses all the mechanisms that render newly developing lymphocytes tolerant to self in primary lymphoid organs. B cell progenitors in the bone marrow and T cell progenitors in the thymus that express antigen receptors with a high affinity for self antigens either undergo further rearrangements of the gene segments encoding their antigen receptors to avoid reactivity to self, or face functional inactivation (anergy), deletion by apoptosis or programming into a suppressive phenotype.

Peripheral tolerance

Peripheral tolerance refers to mechanisms that control the reactivity of self-specific lymphocytes that have escaped central tolerance. These mechanisms include 'active' suppression by cells endowed with immunomodulatory functions (such as regulatory T cells), as well as the induction of anergy or deletion, for example through antigen presentation to T cells in the absence of co-stimulation.

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Joffre, O., Segura, E., Savina, A. et al. Cross-presentation by dendritic cells. Nat Rev Immunol 12, 557–569 (2012). https://doi.org/10.1038/nri3254

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