The peptide-loading complex – antigen translocation and MHC class I loading

2009 ◽  
Vol 390 (8) ◽  
Author(s):  
Christian Schölz ◽  
Robert Tampé
Keyword(s):  
Mhc Class I ◽  
Antigen Processing ◽  
Surface Display ◽  
Class I ◽  
Antigenic Peptides ◽  
Mhc I ◽  
Protein Fragments ◽  
Long Term Stability ◽  
Peptide Loading ◽  
Mhc Class I Molecules

Abstract A large and dynamic membrane-associated machinery orchestrates the translocation of antigenic peptides into the endoplasmic reticulum (ER) lumen for subsequent loading onto major histocompatibility complex (MHC) class I molecules. The peptide-loading complex ensures that only high-affinity peptides, which guarantee long-term stability of MHC I complexes, are presented to T-lymphocytes. Adaptive immunity is dependent on surface display of the cellular proteome in the form of protein fragments, thus allowing efficient recognition of infected or malignant transformed cells. In this review, we summarize recent findings of antigen translocation by the transporter associated with antigen processing and loading of MHC class I molecules in the ER, focusing on the mechanisms involved in this process.

scholarly journals Recent advances in Major Histocompatibility Complex (MHC) class I antigen presentation: Plastic MHC molecules and TAPBPR-mediated quality control

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 158 ◽  
Author(s):  
Andy van Hateren ◽  
Alistair Bailey ◽  
Tim Elliott
Keyword(s):  
Quality Control ◽  
Major Histocompatibility Complex ◽  
Antigen Presentation ◽  
Mhc Class I ◽  
Class I ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
Mhc Class I Molecules

We have known since the late 1980s that the function of classical major histocompatibility complex (MHC) class I molecules is to bind peptides and display them at the cell surface to cytotoxic T cells. Recognition by these sentinels of the immune system can lead to the destruction of the presenting cell, thus protecting the host from pathogens and cancer. Classical MHC class I molecules (MHC I hereafter) are co-dominantly expressed, polygenic, and exceptionally polymorphic and have significant sequence diversity. Thus, in most species, there are many different MHC I allotypes expressed, each with different peptide-binding specificity, which can have a dramatic effect on disease outcome. Although MHC allotypes vary in their primary sequence, they share common tertiary and quaternary structures. Here, we review the evidence that, despite this commonality, polymorphic amino acid differences between allotypes alter the ability of MHC I molecules to change shape (that is, their conformational plasticity). We discuss how the peptide loading co-factor tapasin might modify this plasticity to augment peptide loading. Lastly, we consider recent findings concerning the functions of the non-classical MHC I molecule HLA-E as well as the tapasin-related protein TAPBPR (transporter associated with antigen presentation binding protein-related), which has been shown to act as a second quality-control stage in MHC I antigen presentation.

scholarly journals The first step of peptide selection in antigen presentation by MHC class I molecules

2015 ◽  
Vol 112 (5) ◽  
pp. 1505-1510 ◽  
Author(s):  
Malgorzata A. Garstka ◽  
Alexander Fish ◽  
Patrick H. N. Celie ◽  
Robbie P. Joosten ◽  
George M. C. Janssen ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Peptide Pool ◽  
Class I ◽  
Second Step ◽  
Temperature Sensitive ◽  
Antigenic Peptides ◽  
Mhc I ◽  
Wide Range ◽  
Peptide Complexes ◽  
Mhc Class I Molecules

MHC class I molecules present a variable but limited repertoire of antigenic peptides for T-cell recognition. Understanding how peptide selection is achieved requires mechanistic insights into the interactions between the MHC I and candidate peptides. We find that, at first encounter, MHC I H-2Kb considers a wide range of peptides, including those with expanded N termini and unfitting anchor residues. Discrimination occurs in the second step, when noncanonical peptides dissociate with faster exchange rates. This second step exhibits remarkable temperature sensitivity, as illustrated by numerous noncanonical peptides presented by H-2Kb in cells cultured at 26 °C relative to 37 °C. Crystallographic analyses of H-2Kb–peptide complexes suggest that a conformational adaptation of H-2Kb drives the decisive step in peptide selection. We propose that MHC class I molecules consider initially a large peptide pool, subsequently refined by a temperature-sensitive induced-fit mechanism to retain the canonical peptide repertoire.

scholarly journals Recruitment of MHC Class I Molecules by Tapasin into the Transporter Associated with Antigen Processing-Associated Complex Is Essential for Optimal Peptide Loading

2002 ◽  
Vol 168 (4) ◽  
pp. 1950-1960 ◽  
Author(s):  
Pamela Tan ◽  
Harald Kropshofer ◽  
Ofer Mandelboim ◽  
Nadja Bulbuc ◽  
Günter J. Hämmerling ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Antigen Processing ◽  
Class I ◽  
Peptide Loading ◽  
Mhc Class I Molecules

The Transporter Associated With Antigen Processing: Function and Implications in Human Diseases

2002 ◽  
Vol 82 (1) ◽  
pp. 187-204 ◽  
Author(s):  
Brigitte Lankat-Buttgereit ◽  
Robert Tampé
Keyword(s):  
Cell Surface ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Immune Surveillance ◽  
Class I ◽  
Cell Surface Expression ◽  
Atp Binding ◽  
Binding Motif ◽  
Antigenic Peptides ◽  
Mhc Class I Molecules

The adaptive immune systems have evolved to protect the organism against pathogens encountering the host. Extracellular occurring viruses or bacteria are mainly bound by antibodies from the humoral branch of the immune response, whereas infected or malignant cells are identified and eliminated by the cellular immune system. To enable the recognition, proteins are cleaved into peptides in the cytosol and are presented on the cell surface by class I molecules of the major histocompatibility complex (MHC). The transport of the antigenic peptides into the lumen of the endoplasmic reticulum (ER) and loading onto the MHC class I molecules is an essential process for the presentation to cytotoxic T lymphocytes. The delivery of these peptides is performed by the transporter associated with antigen processing (TAP). TAP is a heterodimer of TAP1 and TAP2, each subunit containing transmembrane domains and an ATP-binding motif. Sequence homology analysis revealed that TAP belongs to the superfamily of ATP-binding cassette transporters. Loss of TAP function leads to a loss of cell surface expression of MHC class I molecules. This may be a strategy for tumors and virus-infected cells to escape immune surveillance. Structure and function of the TAP complex as well as the implications of loss or downregulation of TAP is the topic of this review.

scholarly journals The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy

2021 ◽  
Vol 22 (4) ◽  
pp. 1964
Author(s):  
Akhil Shukla ◽  
Maryse Cloutier ◽  
Madanraj Appiya Santharam ◽  
Sheela Ramanathan ◽  
Subburaj Ilangumaran
Keyword(s):  
Cancer Immunotherapy ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Immune Surveillance ◽  
Class I ◽  
Antigenic Peptides ◽  
Class I Mhc ◽  
Mhc I ◽  
Potential Applications ◽  
Antigen Processing And Presentation

The immune system constantly monitors the emergence of cancerous cells and eliminates them. CD8+ cytotoxic T lymphocytes (CTLs), which kill tumor cells and provide antitumor immunity, select their targets by recognizing tumor antigenic peptides presented by MHC class-I (MHC-I) molecules. Cancer cells circumvent immune surveillance using diverse strategies. A key mechanism of cancer immune evasion is downregulation of MHC-I and key proteins of the antigen processing and presentation machinery (APM). Even though impaired MHC-I expression in cancers is well-known, reversing the MHC-I defects remains the least advanced area of tumor immunology. The discoveries that NLRC5 is the key transcriptional activator of MHC-I and APM genes, and genetic lesions and epigenetic modifications of NLRC5 are the most common cause of MHC-I defects in cancers, have raised the hopes for restoring MHC-I expression. Here, we provide an overview of cancer immunity mediated by CD8+ T cells and the functions of NLRC5 in MHC-I antigen presentation pathways. We describe the impressive advances made in understanding the regulation of NLRC5 expression, the data supporting the antitumor functions of NLRC5 and a few reports that argue for a pro-tumorigenic role. Finally, we explore the possible avenues of exploiting NLRC5 for cancer immunotherapy.

Ligand Design for Specific MHC Class I Molecules on the Cell Surface

2020 ◽  
Author(s):  
Xizheng Sun ◽  
Reika Tokunaga ◽  
Yoko Nagai ◽  
Ryo Miyahara ◽  
Akihiro Kishimura ◽  
...  
Keyword(s):  
Cell Surface ◽  
Mhc Class I ◽  
Targeted Delivery ◽  
Peptide Ligands ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
High Binding Affinity ◽  
Mhc Class I Molecules

<p><a></a><a></a><a>We have validated that ligand peptides designed from antigen peptides could be used for targeting specific major histocompatibility complex class I (MHC-I)</a> molecules on cell surface. To design the ligand peptides, we used reported antigen peptides for each MHC-I molecule with high binding affinity. From the crystal structure of the peptide/MHC-I complexes, we determined a modifiable residue in the antigen peptides and replaced this residue with a lysine with an ε-amine group modified with functional molecules. The designed ligand peptides successfully bound to cells expressing the corresponding MHC-I molecules via exchange of peptides bound to the MHC-I. We demonstrated that the peptide ligands could be used to transport a protein or a liposome to cells expressing the corresponding MHC-I. The present strategy may be useful for targeted delivery to cells overexpressing MHC-I, which have been observed autoimmune diseases.</p>

scholarly journals Magnitude of Alloresponses to MHC Class I/II Expressing Human Cardiac Myocytes Is Limited by Their Intrinsic Ability to Process and Present Antigenic Peptides

2003 ◽  
Vol 10 (2-4) ◽  
pp. 213-226 ◽  
Author(s):  
J. Bruce Sundstrom ◽  
Kimberley C. Jollow ◽  
Veronique Braud ◽  
Francois Villinger ◽  
Andrew J. McMichael ◽  
...  
Keyword(s):  
Cardiac Myocytes ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Influenza A ◽  
Antigen Processing ◽  
Class I ◽  
Target Cells ◽  
Mrna Levels ◽  
Antigenic Peptides ◽  
Ifn Γ

In this investigation we have explored the relationship between the weak allogenicity of cardiac myocytes and their capacity to present allo-antigens by examining the ability of a human cardiac myocyte cell line (W-1) to process and present nominal antigens. W-1 cells (HLA-A*0201 and HLA-DR β1*0301) pulsed with the influenza A matrix 1 (58-66) peptide (M1) were able to serve as targets for the HLA-A*0201 restricted CTL line PG, specific for M1-peptide. However, PG-CTLs were unable to lyse W-1 target cells infected with a recombinant vaccinia virus expressing the M1 protein (M1-VAC). Pretreatment of these M1-VAC targets with IFN-γ partially restored their ability to process and present the M1 peptide. However, parallel studies demonstrated that IFN-γ pretreated W-1's could not process tetanus toxin (TT) or present the TT(830-843) peptide to HLA-DR3 restricted TT-primed T cells. Semi-quantitative RT-PCR measurements revealed significantly lower constitutive levels of expression for MHC class I, TAP-1/2, and LMP-2/7 genes in W-1s that could be elevated by pretreatment with IFN-γ to values equal to or greater than those expressed in EBV-PBLs. However, mRNA levels for the genes encoding MHC class II, Ii, CIITA, and DMA/B were markedly lower in both untreated and IFN-γ pretreated W-1s relative to EBV-PBLs. Furthermore, pulse-chase analysis of the corresponding genes revealed significantly lower protein levels and longer half-life expression in W-1s relative to EBV-PBLs. These results suggest that weak allogenicity of cardiac myocytes may be governed by their limited expression of MHC genes and gene products critical for antigen processing and presentation.

scholarly journals MHC Class I Molecules Exacerbate Viral Infection by Disrupting Type I Interferon Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Simo Xia ◽  
Yijie Tao ◽  
Likun Cui ◽  
Yizhi Yu ◽  
Sheng Xu
Keyword(s):  
Viral Infection ◽  
Mhc Class I ◽  
Class I ◽  
Type I ◽  
Type I Ifn ◽  
Mhc I ◽  
Cell Responses ◽  
Innate Antiviral Immunity ◽  
Mhc Class I Molecules

MHC class I molecules are key in the presentation of antigen and initiation of adaptive CD8+ T cell responses. In addition to its classical activity, MHC I may possess nonclassical functions. We have previously identified a regulatory role of MHC I in TLR signaling and antibacterial immunity. However, its role in innate antiviral immunity remains unknown. In this study, we found a reduced viral load in MHC I-deficient macrophages that was independent of type I IFN production. Mechanically, MHC I mediated viral suppression by inhibiting the type I IFN signaling pathway, which depends on SHP2. Cross-linking MHC I at the membrane increased SHP2 activation and further suppressed STAT1 phosphorylation. Therefore, our data revealed an inhibitory role of MHC I in type I IFN response to viral infection and expanded our understanding of MHC I and antigen presentation.

scholarly journals Physical and Functional Association of the Major Histocompatibility Complex Class I Heavy Chain α3 Domain with the Transporter Associated with Antigen Processing

1998 ◽  
Vol 187 (6) ◽  
pp. 865-874 ◽  
Author(s):  
Kimary Kulig ◽  
Dipankar Nandi ◽  
Igor Bacik ◽  
John J. Monaco ◽  
Stanislav Vukmanovic
Keyword(s):  
Mhc Class Ii ◽  
Heavy Chain ◽  
Antigen Processing ◽  
Surface Expression ◽  
Class I ◽  
Antigenic Peptides ◽  
Histocompatibility Complex ◽  
Cytoplasmic Proteins ◽  
Peptide Loading ◽  
Er Targeting

CD8+ T lymphocytes recognize antigens as short, MHC class I-associated peptides derived by processing of cytoplasmic proteins. The transporter associated with antigen processing translocates peptides from the cytosol into the ER lumen, where they bind to the nascent class I molecules. To date, the precise location of the class I-TAP interaction site remains unclear. We provide evidence that this site is contained within the heavy chain α3 domain. Substitution of a 15 amino acid portion of the H-2Db α3 domain (aa 219-233) with the analogous MHC class II (H-2IAd) β2 domain region (aa 133-147) results in loss of surface expression which can be partially restored upon incubation at 26°C in the presence of excess peptide and β2-microglobulin. Mutant H-2Db (Db219-233) associates poorly with the TAP complex, and cannot present endogenously-derived antigenic peptides requiring TAP-dependent translocation to the ER. However, this presentation defect can be overcome through use of an ER targeting sequence which bypasses TAP-dependent peptide translocation. Thus, the α3 domain serves as an important site of interaction (directly or indirectly) with the TAP complex and is necessary for TAP-dependent peptide loading and class I surface expression.

scholarly journals Recycling MHC class I molecules and endosomal peptide loading

1999 ◽  
Vol 96 (18) ◽  
pp. 10326-10331 ◽  
Author(s):  
M. Gromme ◽  
F. G. C. M. Uytdehaag ◽  
H. Janssen ◽  
J. Calafat ◽  
R. S. van Binnendijk ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Class I ◽  
Peptide Loading ◽  
Mhc Class I Molecules
Sign in / Sign up

Export Citation Format

Share Document