Endosomal compartment: Also a dock for MHC class I peptide loading
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Abstract:
The endosomal compartment, which contains all the components required for loading peptides onto MHC class II molecules, is classically considered to be dedicated to the loading of MHC class II but not MHC class I molecules. However, a report in this issue of the European Journal of Immunology [Eur. J. Immunol. 2014. 44: 774-784], together with other recent studies, shows that the endosomal compartment also supports efficient loading of MHC class I molecules. These results bring a new perspective on the crosstalk between the MHC class II and MHC class I antigen-processing pathways, and may inspire new ideas for the design of vaccines against viruses and tumors.Keywords:
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Antigen processing
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Compartment (ship)
Crosstalk
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Class I molecules of the major histocompatibility complex (MHC) are expressed on the cell surface of almost all nucleated mammalian cells. Their main function is to transport and present peptides, derived from intracellularly degraded proteins, to cytotoxic T cells (CTL). They are also directly involved in the process leading to maturation and selection of a functional CD8+ T cell repertoire. MHC class I molecules consist of a highly polymorphic membrane spanning heavy chain of approximately 45 kD that is non-covalently associated with a light chain, beta 2-microglobulin (beta 2m). Class I molecules bind peptides, usually 8-11 amino acids in length. The majority of the class I-bound peptides are generated in the cytosol and are subsequently translocated into the lumen of the endoplasmic reticulum (ER) through the ATP-dependent transporter associated with antigen processing 1/2 (TAP1/2). Here, we provide an up-to-date review summarizing the most essential parts relating to MHC class I-mediated antigen processing, presentation and T cell selection. A particular emphasis is devoted to the structure of MHC class I molecule, and MHC class I-bound peptides.
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Abstract Tapasin is an integral component of the peptide-loading complex (PLC) important for efficient peptide loading onto MHC class I molecules. We investigated the function of the novel tapasin-related protein, TAPBPR. Like tapasin, TAPBPR is widely expressed, interferon-γ inducible and binds to MHC class I coupled with β2-microglobulin (β2m) in the endoplasmic reticulum. In contrast to tapasin, TAPBPR does not bind ERp57 or calreticulin and is not an integral component of the PLC. β2m is essential for the association between TAPBPR and MHC class I. However, the association between TAPBPR and MHC class I occurs in the absence of a functional PLC, suggesting peptide is not required. Expression of TAPBPR decreases the rate of MHC class I maturation through the secretory pathway and prolongs the association of MHC class I on the PLC. The TAPBPR:MHC class I complex trafficked through the Golgi apparatus, demonstrating a function of TAPBPR beyond the ER/cis-Golgi. The identification of TAPBPR as a novel component of the MHC class I antigen presentation pathway demonstrates that mechanisms controlling MHC class I expression remain incompletely understood.
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The tremendous explosion in the field of MHC research in the last 5 years has significantly advanced our understanding of antigen processing pathways, particularly with regard to details of MHC class II‐mediated antigen presentation. MHC class II molecules at the surface of antigen presenting cells present antigenie peptides to CD4 + T helper cells. However for effective cell surface antigen presentation, a number of highly synchronized events must first take place intracellularly. The monomorphic protein, invariant chain (Ii), is a crucial participant in MHC class II antigen presentation. Acting as a molecular chaperone, this molecule escorts the newly synthesized class II heterodimers from the endoplasmic reticulum into the endosomal system. During this manoeuvre, the interaction of Ii with class II serves to prevent premature association of antigenic peptide. Once the complex reaches the acidic environment of the endosomes, Ii is proteolytically degraded and dissociates, leaving the class II binding site available for binding antigenic peptide derived from exogenous proteins. The final Ii fragment to be displaced. CLIP (class II‐associated invariant chain peptides), must be physically removed from the class II binding groove with assistance from another MHC‐encoded molecule. DM. The interaction of DM with class II also aids in the subsequent rapid loading of high‐affinity antigen‐derived peptides into the MHC class II groove. The stable peptide‐loaded complexes are now ready to exit the endocytic compartments to present their peptide antigen to specific T helper cells at the cell surface.
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Peptides derived from exogenous proteins are presented by both MHC class I and II. Despite extensive study, the features of the endocytic pathway that mediate cross-presentation of exogenous antigens on MHC class I are not entirely understood and difficult to generalize to all proteins. Here, we used dendritic cells and macrophages to examine MHC class I and II presentation of hen egg-white lysozyme (HEL) in different forms, soluble and liposome encapsulated. Soluble HEL or HEL targeted to a late endosomal compartment only allowed for MHC class II presentation, in a process that was blocked by chloroquine and a cathepsin S (CatS) inhibitor; brefeldin A (BFA) also blocked presentation, indicating a requirement for nascent MHC class II. In contrast, liposome-encapsulated HEL targeted to early endosomes entered the MHC class I and II presentation pathways. Cross-presentation of HEL in early endosomal liposomes had several unique features: it was markedly increased by BFA and by blockade of the proteasome or CatS activity, it occurred independently of the transporter associated with antigen processing but required an MHC class I surface-stabilizing peptide, and it was inhibited by chloroquine. Remarkably, chloroquine facilitated MHC class I cross-presentation of soluble HEL and HEL in late endosomal liposomes. Altogether, MHC class I and II presentation of HEL occurred through pathways having distinct molecular and proteolytic requirements. Moreover, MHC class I sampled antigenic peptides from various points along the endocytic route.
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▪ Abstract Class I and class II MHC molecules bind peptides during their biosynthetic maturation and provide a continuously updated display of intracellular and environmental protein composition, respectively, for scrutiny by T cells. Receptor-mediated endocytosis, phagocytosis, and macropinocytosis all contribute to antigen uptake by class II MHC-positive antigen-presenting cells. Capture of antigenic peptides by class II MHC molecules is facilitated because antigen catabolism and class II MHC maturation take place in the same compartments or in communicating compartments of the endosome/lysosome system. These class II MHC-rich, multivesicular endosomes receive incoming antigen and can support not only antigen processing and class II MHC peptide loading but also the export of peptide/class II MHC complexes to the cell surface. A balance between production and destruction of antigenic peptides is achieved by the activity of local proteases and may be influenced by binding of antigen to other proteins both prior to the onset of processing (e.g. antibodies) and during antigen unfolding (e.g. MHC molecules). T cell determinants that can be released for MHC binding without a substantial processing requirement may be able to utilize a distinct minor population of cell surface class II MHC molecules that become available during peripheral recycling. Although peptides derived from exogenous protein sources are usually excluded from presentation on class I MHC molecules, recent evidence shows that this embargo may be lifted in certain professional antigen-presenting cells to increase the spectrum of antigens that may be displayed on class I MHC.
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Abstract Dendritic cells (DCs) progress through distinct maturational phases; immature DCs capture Ag while mature DCs are optimized for Ag presentation. Proper control of immunity requires regulated compartmentalization of MHC class II molecules. We report that DCs also regulate MHC class I trafficking throughout maturation. Although mature human DCs express high levels of surface MHC class I, immature DCs exhibit lower surface levels while retaining MHC class I-peptide complexes in the Golgi. A cell line, KG-1, behaves similarly. We confirm the similarity of KG-1 to DCs by demonstrating its capacity to present exogenous Ags in an MHC class I-restricted fashion to CD8+ T cell hybridomas, a phenomenon called cross-presentation. Biochemical characterization of MHC class I trafficking throughout maturation showed that, in early KG-1 dendritic-like cells, surface arrival of MHC class I-peptide complexes is delayed by their retention in the Golgi. In mature dendritic-like cells, these complexes relocate to the surface and their stability increases, concomitant with up-regulation of costimulatory molecules. Maturation induces qualitative changes in the MHC class I-associated peptide repertoire demonstrated by increased thermostability. The differential processing of MHC class I throughout maturation may prevent premature immune activation while promoting T cell responses in lymph nodes to Ags acquired at sites of inflammation.
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Abstract While endogenous antigens are presented by class I major histocompatibility complex (MHC) molecules, exogenous antigens generally require a means for penetration into the cytosol for processing prior to class I MHC presentation. We have optimized conditions for electroporation as a means to experimentally introduce exogenous antigens into the cytosol, providing a system with a number of advantages for dissecting the class I MHC processing pathway. Presentation was assessed by the response of class I or class II MHC‐restricted T hybridoma cells. Essentially instantaneous antigen delivery by electroporation facilitated kinetic analysis of the class I pathway and investigation of the effects of various inhibitors or hypothermic conditions on class I MHC antigen processing. This pathway was inhibited by weak base amines ( e.g. chloroquine and NH 4 Cl), cycloheximide, and hypothermia (18°C, which inhibits certain intracellular vesicular processing pathways). The electroporation technique provides a simple, consistent approach for rapid cytosolic antigen delivery for analysis of class I MHC processing.
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Abstract: MHC class I antigen presentation refers to the co‐ordinated activities of many intracellular pathways that promote the cell surface appearance of MHC class I/β 2 m heterodimers loaded with a spectrum of self or foreign peptides. These MHC class I peptide complexes form ligands for CD8 positive T cells and NK cells. MHC class I heterodimers are loaded within the endoplasmic reticulum (ER) with peptides derived from intracellular proteins. Alternatively, MHC class I molecules may be loaded with peptides derived from extracellular proteins in a process called MHC class I cross presentation. This pathway is less well defined but can overlap those pathways operating in classical MHC class I presentation and has recently been reviewed elsewhere ( 1 ). This review will address the current concepts regarding the intracellular assembly of MHC class I molecules with their peptide cargo within the ER and their subsequent progress to the cell surface.
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