Journal Article

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

Roche, Paul A., Furuta, Kazuyuki

2015

Overview

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. To play their part in the generation of effective adaptive immune responses, different types of antigen-presenting cell (APC) take up and process antigen in different ways. The length of time that peptide–MHC class II complexes are present on APC surfaces can also vary depending on the cell type. This Review describes the different modes and mechanisms that regulate MHC class II processing and presentation. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/21 / 631/250/21/1293 / 631/250/2504/133 / Amino acids / Animals / Antigen presentation / Antigen Presentation - immunology / Antigen processing / Antigen-presenting cells / Antigen-Presenting Cells - immunology / Antigen-Presenting Cells - metabolism / Antigens / Antigens - immunology / Antigens - metabolism / Autophagy / B cells / Biomedicine / CD4 antigen / Cell activation / Cell Membrane - immunology / Cell Membrane - metabolism / Dendritic cells / Endocytosis / Endosomes / Epitopes - immunology / Health aspects / Histocompatibility Antigens Class II - immunology / Histocompatibility Antigens Class II - metabolism / Humans / Immunology / Lymphocytes T / Lysosomes / Major histocompatibility complex / Peptides / Peptides - immunology / Phagocytosis / Physiological aspects / Protein Transport / Proteolysis / review-article / T cells / Ubiquitin / Ubiquitin-protein ligase