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  • Review Article
  • Published:

The known unknowns of antigen processing and presentation

Key Points

  • Antigen processing and presentation is the mechanism by which whole antigens are degraded and loaded onto MHC molecules for display on the cell surface for recognition by T cells.

  • Both macrophages and dendritic cells (DCs) are considered professional antigen-presenting cells, although DCs possess the unique capacity to activate naive T cells.

  • DCs phagocytose antigens and whole microorganisms and place them into membrane-delimited compartments termed phagosomes. These structures are modified over time and ultimately fuse with lysosomes to form phagolysosomes.

  • Cross-presentation allows DCs to take up antigens from the extracellular environment and present them on MHC class I molecules for CD8+ T-cell activation. Although the exact trafficking patterns of antigens are not known, many hypotheses have been generated, including the recruitment of the endoplasmic reticulum dislocation machinery to the phagosome and protein-independent passing of antigens from the phagosome or phagolysosome into the cytosol.

  • The autophagy machinery is thought to have an important role in the generation of peptide antigens for MHC class II molecules.

Abstract

The principal components of both MHC class I and class II antigen processing and presentation pathways are well known. In dendritic cells, these pathways are tightly regulated by Toll-like-receptor signalling and include features, such as cross-presentation, that are not seen in other cell types. However, the exact mechanisms involved in the subcellular trafficking of antigens remain poorly understood and in some cases are controversial. Recent data suggest that diverse cellular machineries, including autophagy, participate in antigen processing and presentation, although their relative contributions remain to be fully elucidated. Here, we highlight some emerging themes of antigen processing and presentation that we think merit further attention.

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Figure 1: Six steps for loading and trafficking of MHC class I molecules to the cell surface.
Figure 2: Contribution of pathogens and self peptides to loading of MHC class II molecules in dendritic cells.
Figure 3: Additional pathways that might be relevant for antigen processing and presentation by MHC class I molecules in TLR-stimulated dendritic cells.

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Acknowledgements

We thank all members of the Ploegh laboratory for their discussions and K. Artavanis-Tsakonas, E. Frickel and A. Pollington for their critical review of this manuscript. We thank B. Mueller and T. DiCesare for assistance with the original artwork. J.M.V. is funded by NIH K08 AI57999 and MGH DOM start-up funds; A.G.V. is funded by the Boehringer Ingelheim Fonds; H.L.P. is funded by RO1 GM062502, RO1 AI34893, RO1 AI057182 and R37 AI33456.

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The core machinery of autophagy. (PDF 216 kb)

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Glossary

Endolysosomal compartments

Endosomes that have fused with lysosomes. This acidic environment allows degradation of antigens.

Pathogen-associated molecular patterns

Molecular patterns that are found in pathogens but not in mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind the mannose receptor, and various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA, which bind Toll-like receptors.

Endolysosomal tubules

Highly dynamic subcellular structures that eminate from late endocytic–lysosomal and/or phagolysosomal compartments. They are known to contain MHC class II molecules, CD63, CD82 and lysosome-associated membrane protein 1 (LAMP1), and require microtubules for movement.

Endocytic pathway

A trafficking pathway used by all cells for the internalization of molecules from the plasma membrane to the endolysosomes.

Cross-presentation

The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens onto MHC class I molecules. Cross-presentation is important for the initiation of immune responses to viruses that do not infect antigen-presenting cells.

Autophagy

An evolutionarily conserved process in which acidic double-membrane vacuoles, known as autophagosomes, sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation, through fusion to lysosomes. This process does not involve direct transport through the endocytic or vacuolar protein sorting pathways.

Phagosome

A membrane-delimited compartment that confines ingested material such as microorganisms following phagocytosis. Unless counteracted by a pathogen survival strategy, the phagosome matures into a hostile environment (the phagolysosome) that is designed to kill and digest microorganisms by fusing with lysosomes.

Phagolysosome

An intracellular compartment that results from the fusion of phagosomes, which enclose ingested extracellular material, and lysosomes, which contain lytic enzymes.

Tetraspanin

A family of transmembrane proteins that have four transmembrane domains and two extracellular domains of different sizes, which are defined by several conserved amino acids in the transmembrane domains. Their function is not clearly known, but they seem to interact with many other transmembrane proteins and to form large multimeric protein networks.

Immunological synapse

A large junctional structure that is formed at the cell surface between a T cell and an antigen-presenting cell. Important molecules that are involved in T-cell activation — including the T-cell receptor, numerous signal-transduction molecules and molecular adaptors — accumulate in an orderly manner at this site. Immunological synapses are now known to also form between other types of immune cells: for example, between dendritic cells and natural killer cells.

Cathepsins

Proteases that are mostly located in lysosomes and lysosome-like organelles and can be divided into cysteine, aspartate and serine cathepsin subgroups according to their active-site amino acid.

RAB

A cytosolic protein that has GTPase activity, which, in the GTP-bound form, associates with membranes. Different RAB proteins associate with different intracellular compartments — for example, RAB5 associates with early endosomes, RAB7 with late endosomes and RAB11 with recycling endosomes.

Chaperone-mediated autophagy

The import and degradation of soluble cytosolic proteins by chaperone-dependent, direct translocation across the lysosomal membrane.

Microautophagy

The uptake and degradation of cytoplasm by invagination of the lysosomal membrane.

Macroautophagy

(Also known as autophagy). The largely non-specific autophagic sequestration of cytoplasm into a double-membrane-delimited compartment (an autophagosome) of non-lysosomal origin. Note that certain proteins, organelles and pathogens might be selectively degraded via macroautophagy.

Lysosomal degradation

The digestion of macromolecules in lysosomal organelles, which are the terminal organelles of degradative pathways, such as phagosomal, endosomal and autophagy pathways.

Endosomes

Membrane-delimited compartments that contain material ingested by endocytosis. Some material will be recycled to the cell surface whereas some cargo will transit to late endosomes and eventually fuse with lysosomes to form endolysosomes. Endosomes may also fuse with phagosomes to allow maturation of the phagosomal compartment.

Central tolerance

Deletion of self-reactive T cells in the thymus.

Peripheral tolerance

Control of self-reactive T cells in the periphery.

Lipid rafts

Microdomains of the cell membrane that are enriched in sphingolipids. Several membrane-associated signalling molecules are concentrated in these rafts.

Exocytosis

The release of material contained within vesicles by fusion of the vesicles with the plasma membrane.

SNARE

(Soluble-N-ethylmaleimide-sensitive-factor accessory-protein receptor). A class of proteins that is required for membrane fusion events that occur in the course of vesicle trafficking and secretion.

TAP complex

A heterodimeric complex composed of transporter associated with antigen processing 1 (TAP1) and TAP2 in the membrane of the endoplasmic reticulum. The complex transports peptides from the cytoplasm to the endoplasmic reticulum, where peptides can be loaded onto MHC class I molecules. Without these peptides, MHC class I molecules are unstable and are much less likely to transit to the cell surface or to remain there.

Sphingosine

An amino alcohol that can be linked to a fatty acid via the amino group to form the basic structure of sphingolipids.

Necrosis

A form of cell death that results from a decline in cellular ATP or ADP levels below the concentration that is required to maintain cellular organization and integrity.

Aggresome

Proteinaceous inclusion body that forms when the cellular degradation machinery is impaired or overwhelmed and that leads to an accumulation of protein for disposal.

Unfolded-protein response

A response that increases the ability of the endoplasmic reticulum to fold and translocate proteins, decreases the synthesis of proteins, and causes the arrest of the cell cycle and apoptosis.

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Vyas, J., Van der Veen, A. & Ploegh, H. The known unknowns of antigen processing and presentation. Nat Rev Immunol 8, 607–618 (2008). https://doi.org/10.1038/nri2368

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