The Final Touches Make Perfect the Peptide-MHC Class I Repertoire
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Antigen processing
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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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Summary: In this review, we discuss recent data from our laboratory that address two aspects of major histocompatibility complex (MHC) class I‐restricted antigen processing. First, we consider the nature of the peptide‐loading complex, which is the assembly of proteins in the endoplasmic reticulum (ER) into which newly synthesized MHC class I‐β 2 microglobulin (β 2 m) heterodimers are incorporated, and the mechanisms involved in MHC class I assembly and peptide loading that are facilitated by the peptide‐loading complex. Second, we discuss mechanisms of cross‐presentation, the phenomenon whereby extracellular and luminal protein antigens can be processed by antigen‐presenting cells, particularly dendritic cells, and presented by MHC class I molecules to CD8 + T cells. The focus of the discussion is mainly on the human MHC class I system.
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ABSTRACT Major histocompatibility complex class I (MHC-I) molecules are critically important in the host defense against various pathogens through presentation of viral peptides to cytotoxic T lymphocytes (CTLs), a process resulting in the destruction of virus-infected cells. Herpesviruses interfere with CTL-mediated elimination of infected cells by various mechanisms, including inhibition of peptide transport and loading, perturbation of MHC-I trafficking, and rerouting and proteolysis of cell surface MHC-I. In this study, we show that equine herpesvirus type 4 (EHV-4) modulates MHC-I cell surface expression through two different mechanisms. First, EHV-4 can lead to a significant downregulation of MHC-I expression at the cell surface through the product of ORF1, a protein expressed with early kinetics from a gene that is homologous to herpes simplex virus 1 UL56. The EHV-4 UL56 protein reduces cell surface MHC-I as early as 4 h after infection. Second, EHV-4 can interfere with MHC-I antigen presentation, starting at 6 h after infection, by inhibition of the transporter associated with antigen processing (TAP) through its UL49.5 protein. Although pUL49.5 has no immediate effect on overall surface MHC-I levels in infected cells, it blocks the supply of antigenic peptides to the endoplasmic reticulum (ER) and transport of peptide-loaded MHC-I to the cell surface. Taken together, our results show that EHV-4 encodes at least two viral immune evasion proteins: pUL56 reduces MHC-I molecules on the cell surface at early times after infection, and pUL49.5 interferes with MHC-I antigen presentation by blocking peptide transport in the ER.
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CD8+ and CD4+ T lymphocytes recognise peptides stably bound to class I or class II MHC molecules, respectively. These complexes are assembled intracellularly during the biosynthesis and trafficking of MHC molecules. It is now clear that a number of different molecules and macromolecular complexes are drafted in to assist this process. Some of these are chaperones which appear to be dedicated to assisting MHC molecules capture peptides, whilst others may have additional cellular functions. Peptides form an integral part of the final MHC glycoprotein structure and their availability can regulate the kinetics and level of expression of MHC molecules on the cell surface. In vivo, significant time may elapse between generation of peptide/MHC complexes and their recognition by T cells. This requires that the complexes generated are stable and long-lived on the cell surface. Several mechanisms appear to contribute to the generation and display of long-lived complexes. Some pathogens have evolved mechanisms to evade and interfere with presentation of their own antigens. The strategies used are many and varied and are particularly well exemplified by the interaction of viral gene products with the MHC class I assembly pathway. Here, we provide an overview of what is currently known about the cellular biochemistry of antigen processing and the assembly of class I and class II MHC molecules.
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This chapter contains sections titled: Introduction Classical Pathways of Antigen Processing for MHC Presentation Endogenous MHC Class II Antigen Processing of Viral Antigens Autophagic Delivery of Antigens for Lysosomal Degradation and MHC Class II Presentation Similarities Between Sources of MHC Class II Ligands and Autophagy Substrates Overlap Between the Vesicular Transport Pathways of Autophagosomes and MHC Class II Loading Compartments Possible Functions of MHC Class II Presentation after Autophagy in the Immune Control of Viral Infections Future Directions of Research into Endogenous MHC Class II Antigen Processing Summary Acknowledgments References
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The antigen presentation pathway yields peptide-MHC class I complexes on the antigen presenting cell (APC) surface for recognition by appropriate T-cells. Expression of the peptide-MHC complex on APC surface is preceded by several steps that include the generation of peptide fragments in the cytoplasm and their assembly with MHC molecules in the endoplasmic reticulum. It is now clear that MHC binding to optimally processed peptides in the endoplasmic reticulum is obligatory for their stable expression on the cell surface. However, whether a similar obligatory relationship exists between generation of processed peptides and their expression as peptide-MHC on APC surface is not known. Here, we addressed this question by analyzing the processing of ovalbumin (aa257-264, SL8) or influenza nucleoprotein (aa366-374, AM9) analogs. We examined the generation of naturally processed peptides using precursors that did, or did not, contain residues flanking the optimal MHC-binding peptides. By characterizing the peptides generated from these precursors by T-cell stimulation assays and by high performance liquid chromatography analysis, we established that intracellular assembly of peptide-MHC complexes and their expression on the cell surface can occur with peptides that lack flanking residues. The presentation of these endogenously synthesized perfect fit peptides demonstrates that the cleavage of precursor polypeptides is an independent step in the antigen presentation pathway. The antigen presentation pathway yields peptide-MHC class I complexes on the antigen presenting cell (APC) surface for recognition by appropriate T-cells. Expression of the peptide-MHC complex on APC surface is preceded by several steps that include the generation of peptide fragments in the cytoplasm and their assembly with MHC molecules in the endoplasmic reticulum. It is now clear that MHC binding to optimally processed peptides in the endoplasmic reticulum is obligatory for their stable expression on the cell surface. However, whether a similar obligatory relationship exists between generation of processed peptides and their expression as peptide-MHC on APC surface is not known. Here, we addressed this question by analyzing the processing of ovalbumin (aa257-264, SL8) or influenza nucleoprotein (aa366-374, AM9) analogs. We examined the generation of naturally processed peptides using precursors that did, or did not, contain residues flanking the optimal MHC-binding peptides. By characterizing the peptides generated from these precursors by T-cell stimulation assays and by high performance liquid chromatography analysis, we established that intracellular assembly of peptide-MHC complexes and their expression on the cell surface can occur with peptides that lack flanking residues. The presentation of these endogenously synthesized perfect fit peptides demonstrates that the cleavage of precursor polypeptides is an independent step in the antigen presentation pathway.
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Abstract T cell recognition of antigen depends crucially on degradation of protein and binding of protein fragments to MHC molecules which ‘present’ these fragments to T cells. The term ‘antigen presentation’ is used to summarize the complex events of antigen internalization, processing of antigen into peptide fragments, peptide transport, and MHC/peptide interaction until the final appearance of peptide/MHC complexes on the surface of antigen presenting cells. Two separate pathways exist using largely non-overlapping sources of antigen and distinct intracellular compartments for binding to different MHC molecules. Most biosynthesized, intracellular antigens are degraded in the cytosol and peptides are translocated into the endoplasmic reticulum (ER), where they bind to MHC class I molecules and after transport to the cell surface are recognized by class I restricted cytotoxic T cells. The MHC class II presentation pathway does not make use of peptides in the ER since the peptide binding site of MHC class II is blocked by the invariant chain. Instead MHC class II molecules are re-routed to endosomal compartments where the invariant chain is degraded, so that peptides from exogenous proteins that have been internalized by antigen presenting cells (APCs) or from endogenous sources of protein that can enter these compartments bind to invariant chain-free MHC class II for recognition by class II restricted T cells.
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We summarize here our recent studies dealing with the cellular and biochemical analyses of antigen presentation by the class II proteins of the major histocompatibility complex (MHC). Antigen presentation is the process through which immunogenic proteins are prepared for recognition by T lymphocytes. T lymphocytes of the CD4 subset respond to peptides from proteins that are processed in intracellular acidic vesicles of antigen-presenting cells (APCs). Such processed peptides become bound to class II MHC proteins, and together, they form a complex recognizable by CD4 T lymphocytes. CD8 T lymphocytes recognize peptides presented by class I MHC molecules. These peptides originate from proteins degraded in the cytosol, translocated into the endoplasmic reticulum, where they bind to nascent class I MHC molecules, and then transported as a bimolecular complex to the plasma membrane. Therefore, the MHC molecules serve as peptide carriers that rescue peptides from extensive catabolism, with the class I MHC...
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