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.

Identification of MHC-I Accessible Proteins from Salmonella Typhimurium

2001 ◽  
Vol 7 (S2) ◽  
pp. 616-617
Author(s):  
D. Ellefson ◽  
D. Parker ◽  
F. Heffron
Keyword(s):  
Salmonella Typhimurium ◽  
Host Cell ◽  
Antigen Processing ◽  
Bacterial Pathogens ◽  
Immune Surveillance ◽  
Class I ◽  
Whole Genome Analysis ◽  
Class I Mhc ◽  
Mhc I ◽  
Host Interaction

Intracellular bacterial pathogens such as Salmonella typhimurium secrete proteins into the host cell after infection. These proteins alter the normal structural and metabolic machinery of the host cell and benefit the bacterium by facilitating replication and avoidance of host immune surveillance. Since the host cytoplasmic localization of these proteins infers access to the class-I MHC antigen processing and presentation machinery of the host cell, we collectively refer to these proteins as Class- I Accessible Proteins (CAPs).The design of vaccines for new and emerging bacterial pathogens is often constrained by the selection of appropriate and specific antigens. While vaccine design is being greatly aided by whole genome analysis of bacterial pathogens, it has been of limited use in the assignment of function and host subcellular localization of a large percentage of bacterial proteins. in addition, analysis of the bacteria/host interaction is further complicated by the complex lifestyle of the pathogen.

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.

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 Enhanced Delivery of Exogenous Peptides into the Class I Antigen Processing and Presentation Pathway

2002 ◽  
Vol 70 (6) ◽  
pp. 3249-3258 ◽  
Author(s):  
Lolke de Haan ◽  
Arron R. Hearn ◽  
A. Jennifer Rivett ◽  
Timothy R. Hirst
Keyword(s):  
Amino Acid ◽  
Antigen Processing ◽  
Class I ◽  
Protein Antigens ◽  
Class I Mhc ◽  
Mhc I ◽  
C Terminus ◽  
Presentation Pathway ◽  
Antigen Processing And Presentation ◽  
Amino Acid Segment

ABSTRACT Current immunization strategies, using peptide or protein antigens, generally fail to elicit cytotoxic-T-lymphocyte responses, since these antigens are unable to access intracellular compartments where loading of major histocompatibility complex class I (MHC-I) molecules occurs. In an attempt to circumvent this, we investigated whether the GM1 receptor-binding B subunit of Escherichia coli heat-labile toxin (EtxB) could be used to deliver class I epitopes. When a class I epitope was conjugated to EtxB, it was delivered into the MHC-I presentation pathway in a GM1-binding-dependent fashion and resulted in the appearance of MHC-I-epitope complexes at the cell surface. Importantly, we show that the efficiency of EtxB-mediated epitope delivery could be strikingly enhanced by incorporating, adjacent to the class I epitope, a 10-amino-acid segment from the C terminus of the DNA polymerase (Pol) of herpes simplex virus. The replacement of this 10-amino-acid segment by a heterologous sequence or the introduction of specific amino acid substitutions within this segment either abolished or markedly reduced the efficiency of class I epitope delivery. If the epitope was extended at its C terminus, EtxB-mediated delivery into the class I presentation pathway was found to be completely dependent on proteasome activity. Thus, by combining the GM1-targeting function of EtxB with the 10-amino-acid Pol segment, highly efficient delivery of exogenous epitopes into the endogenous pathway of class I antigen processing and presentation can be achieved.

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.

Sign in / Sign up

Export Citation Format

Share Document