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  • Review Article
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The ins and outs of MHC class II-mediated antigen processing and presentation

Nature Reviews Immunology volume 15, pages 203–216 (2015)Cite this article

Subjects

Key Points

  • MHC class II molecules bind antigenic peptides that are generated in endosomal–lysosomal antigen-processing compartments. These peptides are derived from proteins that access these compartments using various endocytic pathways and also as a result of autophagy.

  • Proteolysis in antigen-processing compartments is regulated in antigen-presenting cells (APCs) to favour the formation of antigenic peptides that can bind to MHC class II and to avoid the complete hydrolysis of proteins to very short peptides or to amino acids.

  • Nonspecific endocytosis processes are terminated following dendritic cell (DC) activation, but mature DCs can still internalize antigen by receptor-mediated endocytosis or phagocytosis. Using these pathways, mature DCs can generate peptide–MHC class II complexes and activate naive CD4+ T cells.

  • The formation of antigen-processing compartments is regulated during APC activation. B cell activation results in MHC class II recruitment to endosomes and lysosomes to form these compartments, whereas in DCs, lysosomal proteases relocalize to antigen-processing compartments and enhance antigen proteolysis.

  • APC activation leads to efficient generation of peptide–MHC class II complexes and markedly increases the expression of these complexes on the APC plasma membrane. Increased surface expression of peptide–MHC class II complexes on activated APCs is a result of enhanced MHC class II transcription and/or translation, movement of intracellular peptide–MHC class II complexes to the APC plasma membrane and reduced lysosomal MHC class II degradation.

  • Expression of the E3 ubiquitin ligase MARCH1 by immature APCs promotes rapid turnover of peptide–MHC class II complexes. DC activation terminates MARCH1 expression and ubiquitylation of peptide–MHC class II complexes, thus increasing the half-life of peptide–MHC class II complexes.

Abstract

Antigenic peptide-loaded MHC class II molecules (peptide–MHC class II) are constitutively expressed on the surface of professional antigen-presenting cells (APCs), including dendritic cells, B cells, macrophages and thymic epithelial cells, and are presented to antigen-specific CD4+ T cells. The mechanisms of antigen uptake, the nature of the antigen processing compartments and the lifetime of cell surface peptide–MHC class II complexes can vary depending on the type of APC. It is likely that these differences are important for the function of each distinct APC subset in the generation of effective adaptive immune responses. In this Review, we describe our current knowledge of the mechanisms of uptake and processing of antigens, the intracellular formation of peptide–MHC class II complexes, the intracellular trafficking of peptide–MHC class II complexes to the APC plasma membrane and their ultimate degradation.

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Figure 1: Generation of peptide–MHC class II complexes in antigen-presenting cells.
Figure 2: Pathways of antigen endocytosis in antigen-presenting cells.
Figure 3: Activation of antigen-presenting cells redistributes intracellular MHC class II molecules.
Figure 4: Degradation of peptide–MHC class II complexes in antigen-presenting cells.

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Acknowledgements

The authors acknowledge the many investigators in the field whose primary data could not be cited in this Review owing to space limitations. The authors also thank the anonymous referees who provided excellent advice in the preparation of this manuscript. This work was supported by the Japan Society for the Promotion of Science (to K.F.) and by the Intramural Research Program of the US National Institutes of Health (to P.A.R.).

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Authors and Affiliations

  1. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892-9760, Maryland, USA

    Paul A. Roche

  2. Department of Immunobiology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, 7008530, Japan

    Kazuyuki Furuta

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  1. Paul A. Roche
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Correspondence to Paul A. Roche.

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PowerPoint slides

Glossary

Central tolerance

Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells in the thymus and B cells in the bone marrow that strongly recognize self antigen undergo deletion or marked suppression.

Peripheral tolerance

Refers to mechanisms that control the reactivity of self antigen-specific lymphocytes that have escaped central tolerance. These mechanisms include 'active' suppression by cells that have 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.

Invariant chain

(Ii). A protein that binds to newly synthesized MHC class II molecules and promotes their egress from the endoplasmic reticulum. It blocks the peptide-binding site on nascent MHC class II molecules and targets Ii–MHC class II complexes to late endosomal and lysosomal antigen-processing compartments.

Multivesicular bodies

(MVBs). Forms of late endosomes that contain numerous intraluminal vesicles. MVBs can either fuse with lysosomes (degrading the intraluminal vesicles and associated cargo proteins) or with the plasma membrane (releasing the intracellular vesicles from the cell in the form of exosomes).

Macropinocytosis

A nonspecific endocytosis pathway that facilitates the uptake of extracellular material that can vary in size from small molecules to intact cells. Plasma membrane ruffles entrap extracellular material and the resulting macropinosomes internalize and deliver their cargo to the endosomal–lysosomal pathway.

Clathrin-mediated endocytosis

The specific uptake of extracellular material that binds to membrane receptors and enters the cell through clathrin-coated vesicles. Integral membrane proteins directly bind to clathrin-associated adaptor molecules to facilitate their uptake.

Plasmacytoid DCs

Immature dendritic cells (DCs) with a morphology that resembles that of plasma cells. Plasmacytoid DCs produce large amounts of type I interferons in response to viral infection.

Cross-presentation

The process by which antigen-presenting cells (APCs) load peptides that are derived from extracellular antigens onto MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to pathogens that do not infect APCs.

Macroautophagy

A process by which intracellular proteins, organelles and invading microorganisms are encapsulated in cytosolic vacuoles. These vacuoles (known as autophagosomes) fuse with lysosomes and degrade encapsulated cargo for antigen presentation. Bulk cytoplasmic autophagy occurs as a starvation response.

Immunological synapse

A junctional structure that is formed at the interface between T cells and target cells (including antigen-presenting cells). The molecular organization within this structure concentrates signalling molecules and directs the release of cytokines and lytic granules towards the target cell.

Follicular DCs

Specialized non-haematopoietic stromal cells that reside in the lymphoid follicles and germinal centres. These dendritic cells (DCs) have long dendrites and carry intact antigens on their surface. They are crucial for the optimal selection of B cells that produce antigen-binding antibodies.

Lipid rafts

Structures that arise from phase separation of different plasma membrane lipids as a result of their physical properties. This results in the formation of distinct and stable lipid domains in membranes, which might provide a platform for membrane-associated protein organization.

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Roche, P., Furuta, K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nat Rev Immunol 15, 203–216 (2015). https://doi.org/10.1038/nri3818

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