The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Maja Maric - One of the best experts on this subject based on the ideXlab platform.
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Thiol oxidation and reduction in MHC-restricted Antigen Processing and presentation
Immunologic Research, 1999Co-Authors: Peter Cresswell, Balasubramanian Arunachalam, Naveen Bangia, Tobias Dick, Gundo Diedrich, Eric Hughes, Maja MaricAbstract:Major histocompatibility complex (MHC) class I molecules are assembled in the endoplasmic reticulum (ER) as a trimer of the class I heavy chain, Β^2 microglobulin (Β^2m), and a short peptide. Assembly occurs in a complex with additional noncovalently associated proteins, which include the thiol oxidoreductase, ERp57. This molecule facilitates the formation of the correct disulfide bonds in glycoproteins as they fold in the ER and may play a key role in assembling a stable MHC class I-peptide complex. In the endocytic pathway, reduction of protein disulfide bonds is important for the generation of MHC class II-peptide complexes. This process is catalyzed by a γ-interferon-inducible thiol reductase (GILT). The possible requirement for catalysis of disulfide bond formation in MHC class I-restricted Antigen Processing and the known requirement for disulfide bond reduction in MHC class II-restricted Antigen Processing present interesting examples of the adaptation of cellular “housekeeping” functions to facilitate immune responses.
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Thiol oxidation and reduction in MHC-restricted Antigen Processing and presentation.
Immunologic research, 1999Co-Authors: P Cresswell, Balasubramanian Arunachalam, Naveen Bangia, Tobias Dick, Gundo Diedrich, Eric Hughes, Maja MaricAbstract:Major histocompatibility complex (MHC) class I molecules are assembled in the endoplasmic reticulum (ER) as a trimer of the class I heavy chain, beta2 microglobulin (beta2m), and a short peptide. Assembly occurs in a complex with additional noncovalently associated proteins, which include the thiol oxidoreductase, ERp57. This molecule facilitates the formation of the correct disulfide bonds in glycoproteins as they fold in the ER and may play a key role in assembling a stable MHC class I-peptide complex. In the endocytic pathway, reduction of protein disulfide bonds is important for the generation of MHC class II-peptide complexes. This process is catalyzed by a gamma-interferon-inducible thiol reductase (GILT). The possible requirement for catalysis of disulfide bond formation in MHC class I-restricted Antigen Processing and the known requirement for disulfide bond reduction in MHC class II-restricted Antigen Processing present interesting examples of the adaptation of cellular "housekeeping" functions to facilitate immune responses.
Jonathan W. Yewdell - One of the best experts on this subject based on the ideXlab platform.
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Topley and Wilson's Microbiology and Microbial Infections - MHC Class I Antigen Processing System
Topley & Wilson's Microbiology and Microbial Infections, 2010Co-Authors: Jonathan W. YewdellAbstract:1 Evolutionary Context: Overview of the Adaptive Cellular Immune System 2 Antigen Processing: Step by Step Keywords: MHC class I Antigen Processing system; adaptive cellular immune system; DCs, role in generating CD8+ T-cell responses; Antigen Processing-step by step; class I peptide ligands and binding rules; exogenous peptide presentation and practical issues; class I assembly and surface expression; nonproteasomal cytosolic proteases in Antigen Processing
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Two Novel Routes of Transporter Associated with Antigen Processing (TAP)-independent Major Histocompatibility Complex Class I Antigen Processing
The Journal of experimental medicine, 1997Co-Authors: Heidi Link Snyder, Jack R. Bennink, Igor Bacik, Grainne M. Kearns, Timothy W. Behrens, Thomas Bächi, Marian Orlowski, Jonathan W. YewdellAbstract:Jaw1 is an endoplasmic reticulum (ER) resident protein representative of a class of proteins post translationally inserted into membranes via a type II membrane anchor (cytosolic NH2 domain, lumenal COOH domain) in a translocon-independent manner. We found that Jaw1 can efficiently deliver a COOH-terminal Antigenic peptide to class I molecules in transporter associated with Antigen Processing (TAP)-deficient cells or cells in which TAP is inactivated by the ICP47 protein. Peptide delivery mediated by Jaw1 to class I molecules was equal or better than that mediated by the adenovirus E3/19K glycoprotein signal sequence, and was sufficient to enable cytofluorographic detection of newly recruited thermostabile class I molecules at the surface of TAP-deficient cells. Deletion of the transmembrane region retargeted Jaw1 from the ER to the cytosol, and severely, although incompletely, abrogated its TAP-independent peptide carrier activity. Use of different protease inhibitors revealed the involvement of a nonproteasomal protease in the TAP-independent activity of cytosolic Jaw1. These findings demonstrate two novel TAP-independent routes of Antigen Processing; one based on highly efficient peptide liberation from the COOH terminus of membrane proteins in the ER, the other on delivery of a cytosolic protein to the ER by an unknown route.
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Identification of human cancers deficient in Antigen Processing.
The Journal of experimental medicine, 1993Co-Authors: Nicholas P. Restifo, Jonathan W. Yewdell, Fernando Esquivel, Yutaka Kawakami, James J. Mulé, Steven A. Rosenberg, Jack R. BenninkAbstract:Intracellular Antigens must be processed before presentation to CD8+ T cells by major histocompatibility complex (MHC) class I molecules. Using a recombinant vaccinia virus (Vac) to transiently express the Kd molecule, we studied the Antigen Processing efficiency of 26 different human tumor lines. Three cell lines, all human small cell lung carcinoma, consistently failed to process endogenously synthesized proteins for presentation to Kd-restricted, Vac-specific T cells. Pulse-chase experiments showed that MHC class I molecules were not transported by these cell lines from the endoplasmic reticulum to the cell surface. This finding suggested that peptides were not available for binding to nascent MHC molecules in the endoplasmic reticulum. Northern blot analysis of these cells revealed low to nondetectable levels of mRNAs for MHC-encoded proteasome components LMP-7 and LMP-2, as well as the putative peptide transporters TAP-1 and TAP-2. Treatment of cells with interferon gamma enhanced expression of these mRNAs and reversed the observed functional and biochemical deficits. Our findings suggest that downregulation of Antigen Processing may be one of the strategies used by tumors to escape immune surveillance. Potential therapeutic applications of these findings include enhancing Antigen Processing at the level of the transcription of MHC-encoded proteasome and transporter genes.
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The multiple uses of viruses for studying Antigen Processing
Seminars in Virology, 1993Co-Authors: Jonathan W. Yewdell, Nicholas P. Restifo, Fernando Esquivel, Rob Anderson, Josephine H. Cox, Laurence C. Eisenlohr, Cheryl Lapham, Jack R. BenninkAbstract:Abstract CD8+ T lymphocytes play an important role in limiting the replication of viruses and other intracellular parasites. It has recently been appreciated that higher eukaryotic cells have evolved a sophisticated mechanism for generating Antigenic determinants and transporting them to the cell surface for recognition by CD8+ lymphocytes. In this paper we discuss how viruses have been used in the past and might be used in the future to delineate the cellular Antigen Processing machinery.
Hakim Djaballah - One of the best experts on this subject based on the ideXlab platform.
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Antigen Processing by proteasomes: insights into the molecular basis of crypticity.
Molecular Biology Reports, 1997Co-Authors: Hakim DjaballahAbstract:Eight to eleven amino acid residues are the sizes of predominant peptides found to be associated with MHC class I molecules. Proteasomes have been implicated in Antigen Processing and generation of such peptides. Advanced methodologies in peptide elution together with sequence determination have led to the characterisation of MHC class I binding motifs. More recently, screening of random peptide phage display libraries and synthetic combinatorial peptide libraries have also been successfully used. This has led to the development and use of predictive algorithms to screen Antigens for potential CTL epitopes. Not all predicted epitopes will be generated in vivo and the emerging picture suggests differential presentation of predicted CTL epitopes ranging from cryptic to immunodominant. The scope of this review is to discuss Antigen Processing by proteasomes, and to put forward a hypothesis that the molecular basis of immunogenicity can be a function of proteasomal Processing. This may explain how pathogens and tumours are able to escape immunosurveillance by altering sequences required by proteasomes for epitope generation. Abbreviations: CTL – cytotoxic T lymphocytes; DRiPs – defective ribosomal products; ER – endoplasmic reticulum; Hsps – heat shock proteins; LMP – low molecular weight peptide; MHC – major histocompatibility complex; TAP – transporter associated with Antigen Processing.
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Antigen Processing by proteasomes: insights into the molecular basis of crypticity.
Molecular biology reports, 1997Co-Authors: Hakim DjaballahAbstract:Eight to eleven amino acid residues are the sizes of predominant peptides found to be associated with MHC class I molecules. Proteasomes have been implicated in Antigen Processing and generation of such peptides. Advanced methodologies in peptide elution together with sequence determination have led to the characterisation of MHC class I binding motifs. More recently, screening of random peptide phage display libraries and synthetic combinatorial peptide libraries have also been successfully used. This has led to the development and use of predictive algorithms to screen Antigens for potential CTL epitopes. Not all predicted epitopes will be generated in vivo and the emerging picture suggests differential presentation of predicted CTL epitopes ranging from cryptic to immunodominant. The scope of this review is to discuss Antigen Processing by proteasomes, and to put forward a hypothesis that the molecular basis of immunogenicity can be a function of proteasomal Processing. This may explain how pathogens and tumours are able to escape immunosurveillance by altering sequences required by proteasomes for epitope generation.
Christian Münz - One of the best experts on this subject based on the ideXlab platform.
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Monitoring Antigen Processing for MHC Presentation via Macroautophagy.
Methods in molecular biology (Clifton N.J.), 2019Co-Authors: Monique Gannagé, Rosa Barreira Da Silva, Christian MünzAbstract:Macroautophagy has recently emerged as an important catabolic process involved not only in innate immunity but also in adaptive immunity. Initially described to deliver intracellular Antigens to MHC class II loading compartments, its molecular machinery has now also been described to impact the delivery of extracellular Antigens to MHC class II loading compartments through the noncanonical use of the macroautophagy machinery during LC3-associated phagocytosis (LAP). Therefore, in pathological situations (viral or bacterial infections, tumorigenesis) the pathway might be involved in shaping CD4$^{+}$ T cell responses.In this chapter we describe three basic experiments for the monitoring and manipulation of macroautophagic Antigen Processing toward MHC class II presentation through the canonical pathway. Firstly, we will discuss how to monitor autophagic flux and autophagosome fusion with MHC class II loading compartments. Secondly, we will show how to target proteins to autophagosomes in order to monitor macroautophagy dependent Antigen Processing via their enhanced presentation on MHC class II molecules to CD4$^{+}$ T cells. And finally, we will describe how macroautophagy can be silenced in Antigen presenting cells, like human monocyte-derived dendritic cells (DCs).
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Autophagy proteins in Antigen Processing for presentation on MHC molecules.
Immunological reviews, 2016Co-Authors: Christian MünzAbstract:Summary Autophagy describes catabolic pathways that deliver cytoplasmic constituents for lysosomal degradation. Since major histocompatibility complex (MHC) molecules sample protein degradation products and present them to T cells for adaptive immunity, it is maybe not too surprising that autophagy contributes to this protein Antigen Processing for MHC presentation. However, the recently recognized breath of pathways, by which autophagy contributes to MHC Antigen Processing, is exciting. Macroautophagy does not only seem to deliver intracellular but facilitates also extracellular Antigen Processing by lysosomal hydrolysis for MHC class II presentation. Moreover, even MHC class I molecules that usually display proteasomal products are regulated by macroautophagy, probably using a pool of these molecules outside the endoplasmic reticulum, where MHC class I molecules are loaded with peptide during canonical MHC class I Antigen Processing. This review aims to summarize these recent developments and point out gaps of knowledge, which should be filled by further investigation, in order to harness the different Antigen-Processing pathways via autophagy for vaccine improvement.
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Antigen Processing for MHC presentation via macroautophagy.
Methods in molecular biology (Clifton N.J.), 2012Co-Authors: Monique Gannagé, Rosa Barreira Da Silva, Christian MünzAbstract:Macroautophagy has recently emerged as an important catabolic process involved not only in innate immunity but also in adaptive immunity. Initially described to deliver intracellular Antigens to MHC class II loading compartments, its molecular machinery has now also been described to enhance the delivery of extracellular Antigens to MHC class II loading compartments by accelerating phagosome maturation. Therefore in pathological situations (viral or bacterial infections, tumorigenesis) the pathway might be involved in shaping CD4(+) T cell responses.In this chapter we describe three basic experiments for the monitoring and manipulation of macroautophagic Antigen Processing towards MHC class II presentation. Firstly, we will discuss how to monitor autophagic flux and autophagosome fusion with MHC class II loading compartments. Secondly, we will show how to target proteins to autophagosomes in order to monitor macroautophagy-dependent Antigen Processing via their enhanced presentation on MHC class II molecules to CD4(+) T cells. And finally, we will describe how macroautophagy can be silenced in Antigen presenting cells, like human monocyte-derived dendritic cells (DCs).
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Antigen Processing for MHC Class II Presentation via Autophagy.
Frontiers in immunology, 2012Co-Authors: Christian MünzAbstract:T cells recognize proteolytic fragments of Antigens that are presented to them on major histocompatibility complex (MHC) molecules. MHC class I molecules present primarily products of proteasomal proteolysis to CD8+ T cells, while MHC class II molecules display mainly degradation products of lysosomes for stimulation of CD4+ T cells. Macroautophagy delivers intracellular proteins to lysosomal degradation, and contributes in this fashion to the pool of MHC class II displayed peptides. Both self- and pathogen-derived MHC class II ligands are generated by this pathway. In addition, however, recent evidence points also to regulation of extracellular Antigen Processing by macroautophagy. In this review, I will discuss these two aspects of Antigen Processing for MHC class II presentation via macroautophagy, namely its influence on intracellular and extracellular Antigen presentation to CD4+ T cells.
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Antigen Processing by macroautophagy for MHC presentation.
Frontiers in immunology, 2011Co-Authors: Christian MünzAbstract:T cells recognize Antigen fragments, presented to them by MHC molecules. It lies in the interest of the immune system to display a maximal diversity of these peptides and utilize all catabolic processes to generate them. Macroautophagy, a pathway that delivers cytoplasmic constituents for lysosomal degradation, is no exception. In recent years, it has become apparent that macroautophagy assists in intra- and extracellular Antigen Processing for MHC class II presentation to CD4+ helper T cells. Surprisingly, however, macroautophagy also assists in Antigen packaging for better cross-presentation on MHC molecules of bystander cells, which could be consistent with its role in unconventional protein secretion. These three pathways of Antigen Processing for MHC presentation via macroautophagy will be discussed in this review and cell biological aspects will be high-lighted that might explain, how the molecular machinery of macroautophagy might assist these diverse Antigen Processing pathways.
Jack R. Bennink - One of the best experts on this subject based on the ideXlab platform.
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Two Novel Routes of Transporter Associated with Antigen Processing (TAP)-independent Major Histocompatibility Complex Class I Antigen Processing
The Journal of experimental medicine, 1997Co-Authors: Heidi Link Snyder, Jack R. Bennink, Igor Bacik, Grainne M. Kearns, Timothy W. Behrens, Thomas Bächi, Marian Orlowski, Jonathan W. YewdellAbstract:Jaw1 is an endoplasmic reticulum (ER) resident protein representative of a class of proteins post translationally inserted into membranes via a type II membrane anchor (cytosolic NH2 domain, lumenal COOH domain) in a translocon-independent manner. We found that Jaw1 can efficiently deliver a COOH-terminal Antigenic peptide to class I molecules in transporter associated with Antigen Processing (TAP)-deficient cells or cells in which TAP is inactivated by the ICP47 protein. Peptide delivery mediated by Jaw1 to class I molecules was equal or better than that mediated by the adenovirus E3/19K glycoprotein signal sequence, and was sufficient to enable cytofluorographic detection of newly recruited thermostabile class I molecules at the surface of TAP-deficient cells. Deletion of the transmembrane region retargeted Jaw1 from the ER to the cytosol, and severely, although incompletely, abrogated its TAP-independent peptide carrier activity. Use of different protease inhibitors revealed the involvement of a nonproteasomal protease in the TAP-independent activity of cytosolic Jaw1. These findings demonstrate two novel TAP-independent routes of Antigen Processing; one based on highly efficient peptide liberation from the COOH terminus of membrane proteins in the ER, the other on delivery of a cytosolic protein to the ER by an unknown route.
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Identification of human cancers deficient in Antigen Processing.
The Journal of experimental medicine, 1993Co-Authors: Nicholas P. Restifo, Jonathan W. Yewdell, Fernando Esquivel, Yutaka Kawakami, James J. Mulé, Steven A. Rosenberg, Jack R. BenninkAbstract:Intracellular Antigens must be processed before presentation to CD8+ T cells by major histocompatibility complex (MHC) class I molecules. Using a recombinant vaccinia virus (Vac) to transiently express the Kd molecule, we studied the Antigen Processing efficiency of 26 different human tumor lines. Three cell lines, all human small cell lung carcinoma, consistently failed to process endogenously synthesized proteins for presentation to Kd-restricted, Vac-specific T cells. Pulse-chase experiments showed that MHC class I molecules were not transported by these cell lines from the endoplasmic reticulum to the cell surface. This finding suggested that peptides were not available for binding to nascent MHC molecules in the endoplasmic reticulum. Northern blot analysis of these cells revealed low to nondetectable levels of mRNAs for MHC-encoded proteasome components LMP-7 and LMP-2, as well as the putative peptide transporters TAP-1 and TAP-2. Treatment of cells with interferon gamma enhanced expression of these mRNAs and reversed the observed functional and biochemical deficits. Our findings suggest that downregulation of Antigen Processing may be one of the strategies used by tumors to escape immune surveillance. Potential therapeutic applications of these findings include enhancing Antigen Processing at the level of the transcription of MHC-encoded proteasome and transporter genes.
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The multiple uses of viruses for studying Antigen Processing
Seminars in Virology, 1993Co-Authors: Jonathan W. Yewdell, Nicholas P. Restifo, Fernando Esquivel, Rob Anderson, Josephine H. Cox, Laurence C. Eisenlohr, Cheryl Lapham, Jack R. BenninkAbstract:Abstract CD8+ T lymphocytes play an important role in limiting the replication of viruses and other intracellular parasites. It has recently been appreciated that higher eukaryotic cells have evolved a sophisticated mechanism for generating Antigenic determinants and transporting them to the cell surface for recognition by CD8+ lymphocytes. In this paper we discuss how viruses have been used in the past and might be used in the future to delineate the cellular Antigen Processing machinery.