An improved assembly assay for peptide binding to HLA-B*2705 and H-2Kk class I MHC molecules
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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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Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
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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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The efficiency of antigen ( A g) processing by dendritic cells ( DC s) is vital for the strength of the ensuing T ‐cell responses. Previously, we and others have shown that in comparison to protein vaccines, vaccination with synthetic long peptides ( SLP s) has shown more promising (pre‐)clinical results. Here, we studied the unknown mechanisms underlying the observed vaccine efficacy of SLP s. We report an in vitro processing analysis of SLP s for MHC class I and class II presentation by murine DC s and human monocyte‐derived DC s. Compared to protein, SLP s were rapidly and much more efficiently processed by DC s, resulting in an increased presentation to CD 4 + and CD 8 + T cells. The mechanism of access to MHC class I loading appeared to differ between the two forms of A g. Whereas whole soluble protein A g ended up largely in endolysosomes, SLP s were detected very rapidly outside the endolysosomes after internalization by DC s, followed by proteasome‐ and transporter associated with Ag processing‐dependent MHC class I presentation. Compared to the slower processing route taken by whole protein A gs, our results indicate that the efficient internalization of SLP s, accomplished by DC s but not by B or T cells and characterized by a different and faster intracellular routing, leads to enhanced CD 8 + T ‐cell activation.
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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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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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Antigen presentation is prinicipally a function of MHC molecules, assisted by a number of adhesion and co-stimulatory molecules not immediately involved in antigen handling. Each MHC molecule, class I or class II, presents peptides derived from self or foreign proteins according to individual rules which have been elucidated in detail for several dozens of MHC molecules. How such peptides are produced by the antigen processing devices in a cell is less well understood; for class I-restricted processing, proteasomes, TAP molecules and probably chaperones are key players whereas the invariant chain, DM molecules, and a number of proteins are central to class II loading. Currently of special interest are alternative class I-loading pathways, nonclassical MHC molecules, the way NK cells recognize their targets, and the use of MHC peptide specificities for applications in immune therapy.
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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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