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36 results on '"Gould, Keith G."'

3. Endoplasmic Reticulum Degradation–Enhancing α-Mannosidase–like Protein 1 Targets Misfolded HLA–B27 Dimers for Endoplasmic Reticulum–Associated Degradation

Author

Guiliano, David B., Fussell, Helen, Lenart, Izabela, Tsao, Edward, Nesbeth, Darren, Fletcher, Adam J., Campbell, Elaine C., Yousaf, Nasim, Williams, Sarah, Santos, Susana, Cameron, Amy, Towers, Greg J., Kellam, Paul, Hebert, Daniel N., Gould, Keith G., Powis, Simon J., and Antoniou, Antony N.

Published
2014
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8. Endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 1 targets misfolded HLA-B27 dimers for endoplasmic reticulum-associated degradation

Author

Guiliano, David B, Fussell, Helen, Lenart, Izabela, Tsao, Edward, Nesbeth, Darren, Fletcher, Adam J, Campbell, Elaine C, Yousaf, Nasim, Williams, Sarah, Santos, Susana, Cameron, Amy, Towers, Greg J, Kellam, Paul, Hebert, Daniel N, Gould, Keith G, Powis, Simon J, and Antoniou, Antony N

Subjects
musculoskeletal diseases, C130, C550
Abstract

OBJECTIVE\ud \ud HLA-B27 forms misfolded heavy chain dimers, which may predispose individuals to inflammatory arthritis by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This study was undertaken to define the role of the UPR-induced ER-associated degradation (ERAD) pathway in the disposal of HLA-B27 dimeric conformers.\ud \ud METHODS\ud \ud HeLa cell lines expressing only 2 copies of a carboxy-terminally Sv5-tagged HLA-B27 were generated. The ER stress-induced protein ER degradation-enhancing α-mannosidase-like protein 1 (EDEM1) was overexpressed by transfection, and dimer levels were monitored by immunoblotting. EDEM1, the UPR-associated transcription factor X-box binding protein 1 (XBP-1), the E3 ubiquitin ligase hydroxymethylglutaryl-coenzyme A reductase degradation 1 (HRD1), and the degradation-associated proteins derlin 1 and derlin 2 were inhibited using either short hairpin RNA or dominant-negative mutants. The UPR-associated ERAD of HLA-B27 was confirmed using ER stress-inducing pharamacologic agents in kinetic and pulse chase assays.\ud \ud RESULTS\ud \ud We demonstrated that UPR-induced machinery can target HLA-B27 dimers and that dimer formation can be controlled by alterations to expression levels of components of the UPR-induced ERAD pathway. HLA-B27 dimers and misfolded major histocompatibility complex class I monomeric molecules bound to EDEM1 were detected, and overexpression of EDEM1 led to inhibition of HLA-B27 dimer formation. EDEM1 inhibition resulted in up-regulation of HLA-B27 dimers, while UPR-induced ERAD of dimers was prevented in the absence of EDEM1. HLA-B27 dimer formation was also enhanced in the absence of XBP-1, HRD1, and derlins 1 and 2.\ud \ud CONCLUSION\ud \ud The present findings indicate that the UPR ERAD pathway can dispose of HLA-B27 dimers, thus presenting a potential novel therapeutic target for modulation of HLA-B27-associated inflammatory disease.

Published
2014

10. Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide–MHC

Author

Hoerter, John A.H., primary, Brzostek, Joanna, additional, Artyomov, Maxim N., additional, Abel, Steven M., additional, Casas, Javier, additional, Rybakin, Vasily, additional, Ampudia, Jeanette, additional, Lotz, Carina, additional, Connolly, Janet M., additional, Chakraborty, Arup K., additional, Gould, Keith G., additional, and Gascoigne, Nicholas R.J., additional

Published
2013
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11. LMP2+ proteasome are required for the presentation of specific antigens to cytotoxic T lymphocyte

Author

SIBILLE, CATHERINE, Gould, Keith G., Willard-Gallo, Karen, Thomson, Stuart, Rivett, Jennifer, Powis, Simon, Butcher, Geoffrey W., De Baetselier, Patrick, Cellular and Molecular Immunology, and Vrije Universiteit Brussel

Subjects
stomatognathic diseases, otorhinolaryngologic diseases
Abstract

BACKGROUND: Major histocompatibility complex (MHC) class I molecules present short peptides generated by intracellular protein degradation to cytotoxic T lymphocytes (CTL). The multisubunit, non-lysosomal proteinases known as proteasomes have been implicated in the generation of these peptides. Two interferon-gamma (IFN-gamma)-inducible proteasome subunits, LMP2 and LMP7, are encoded within the MHC gene cluster in a region associated with antigen presentation. The incorporation of these LMP subunits into proteasomes may alter their activity so as to favour the generation of peptides able to bind to MHC class I molecules. It has been difficult, however, to demonstrate a specific requirement for LMP2 or LMP7 in the presentation of peptide epitopes to CTL. RESULTS: We describe a T-cell lymphoma, termed SP3, that displays a novel selective defect in MHC class I-restricted presentation of influenza virus antigens. Of the MHC-encoded genes implicated in the class I pathway, only LMP2 is underexpressed in SP3 cells. Expression of IFN-gamma in transfected SP3 cells simultaneously restores LMP2 expression and antigen presentation to CTL. Expression of antisense-LMP2 mRNA in these IFN-gamma-transfected cells selectively represses antigen recognition and the induction of surface class I MHC expression. Moreover, the expression of this antisense-LMP2 mRNA in L929 fibroblast cells, which constitutively express LMP2 and have no presentation defect, blocks the presentation of the same influenza virus antigens that SP3 cells are defective in presenting. CONCLUSIONS: Our results show that the LMP2 proteasome subunit can directly influence both MHC class I-restricted antigen presentation and class I surface expression.

Published
1995

18. Human T Cell Lymphotropic Virus (HTLV) Type–1–Specific CD8+T Cells: Frequency and Immunodominance Hierarchy

Author

Goon, Peter K. C., primary, Biancardi, Alix, additional, Fast, Noam, additional, Igakura, Tadahiko, additional, Hanon, Emmanuel, additional, Mosley, Angelina J., additional, Asquith, Becca, additional, Gould, Keith G., additional, Marshall, Sara, additional, Taylor, Graham P., additional, and Bangham, Charles R. M., additional

Published
2004
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19. High Circulating Frequencies of Tumor Necrosis Factor Alpha- and Interleukin-2-Secreting Human T-Lymphotropic Virus Type 1 (HTLV-1)-Specific CD4 + T Cells in Patients with HTLV-1-Associated Neurological Disease

Author

Goon, Peter K. C., primary, Igakura, Tadahiko, additional, Hanon, Emmanuel, additional, Mosley, Angelina J., additional, Asquith, Becca, additional, Gould, Keith G., additional, Taylor, Graham P., additional, Weber, Jonathan N., additional, and Bangham, Charles R. M., additional

Published
2003
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28. Human T Cell Lymphotropic Virus (HTLV) Type-1-Specific CD8+ T Cells: Frequency and Immunodominance Hierarchy.

Author

Goon, Peter K. C., Biancardi, Mix, Fast, Noam, Igakura, Tadahiko, Hanon, Emmanuel, Mosley, Angelina J., Asquith, Becca, Gould, Keith G., Marshall, Sara, Taylor, Graham P., and Bangham, Charles R. M.

Subjects
LYMPHOCYTES, T cells, VIRUSES, ANTINEOPLASTIC agents, ANTIVIRAL agents, VIRUS inhibitors
Abstract

Human T cell lymphotropic virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We used interferon-γ enzyme-linked immunospot assays with overlapping peptides spanning the entire HTLV-1 proteome to test whether the HTLV-1-specific CD8+ T cells differed significantly in frequency or immunodominance hierarchy between patients with HAM/TSP and asymptomatic carriers and whether the frequency correlated with provirus load. Tax was the immunodominant target antigen. There was no significant qualitative or quantitative difference in the HTLV-1-specific CD8+ T cell response between the 2 groups. Virus-specific CD8+ T cell frequency alone does not indicate the effectiveness of the cytotoxic T lymphocyte response in controlling provirus load at equilibrium. [ABSTRACT FROM AUTHOR]

Published
2004
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30. Influenza A virus—a model for viral antigen presentation to cytotoxic T lymphocytes

Author

Parker*†, Claire E. and Gould*, Keith G.

Abstract

Human influenza A virus is characterized by its high degree of variability and by its ability to cause frequent epidemics of disease. Most of the variation occurs in the two surface glycoproteins of the virus, against which protective antibodies are directed. In contrast, the strong MHC class I-restricted CTL response to infection with virus is predominantly specific for internal viral proteins which are relatively well conserved, and is cross-reactive between different strains of influenza A virus. However, the natural evolution of influenza viruses is largely driven by selection with antibody, with no firm evidence of selection by CTL. In normal individuals influenza virus produces an acute, localized infection, and this in part may reflect an inability to escape the CTL response.

Published
1996
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35. Different MHC class I heavy chains compete with each other for folding independently of beta 2-microglobulin and peptide.

Author

Tourdot S, Nejmeddine M, Powis SJ, and Gould KG

Subjects
ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP Binding Cassette Transporter, Subfamily B, Member 3, ATP-Binding Cassette Transporters metabolism, Animals, Antigen Presentation genetics, CHO Cells, Cell Line, Cell Line, Tumor, Cell Membrane immunology, Cell Membrane metabolism, Cricetinae, Down-Regulation immunology, Endoplasmic Reticulum genetics, Endoplasmic Reticulum metabolism, H-2 Antigens genetics, Mice, Mice, Transgenic, Protein Binding genetics, Protein Binding immunology, Protein Processing, Post-Translational genetics, Protein Processing, Post-Translational immunology, Protein Subunits genetics, Protein Transport genetics, Protein Transport immunology, Transfection, H-2 Antigens biosynthesis, Peptides chemistry, Protein Folding, Protein Subunits biosynthesis, beta 2-Microglobulin metabolism
Abstract

We reported previously that different MHC class I molecules can compete with each other for cell surface expression in F(1) hybrid and MHC class I transgenic mice. In this study, we show that the competition also occurs in transfected cell lines, and investigate the mechanism. Cell surface expression of an endogenous class I molecule in Chinese hamster ovary (CHO) cells was strongly down-regulated when the mouse K(d) class I H chain was introduced by transfection. The competition occurred only after K(d) protein translation, not at the level of RNA, and localization studies of a CHO class I-GFP fusion showed that the presence of K(d) caused retention of the hamster class I molecule in the endoplasmic reticulum. The competition was not for beta(2)-microglobulin, because a single chain version of K(d) that included mouse beta(2)-microglobulin also had a similar effect. The competition was not for association with TAP and loading with peptide, because a mutant form of the K(d) class I H chain, not able to associate with TAP, caused the same down-regulation of hamster class I expression. Moreover, K(d) expression led to a similar level of competition in TAP2-negative CHO cells. Competition for cell surface expression was also found between different mouse class I H chains in transfected mouse cells, and this competition prevented association of the H chain with beta(2)-microglobulin. These unexpected new findings show that different class I H chains compete with each other at an early stage of the intracellular assembly pathway, independently of beta(2)-microglobulin and peptide.

Published
2005
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36. High circulating frequencies of tumor necrosis factor alpha- and interleukin-2-secreting human T-lymphotropic virus type 1 (HTLV-1)-specific CD4+ T cells in patients with HTLV-1-associated neurological disease.

Author

Goon PK, Igakura T, Hanon E, Mosley AJ, Asquith B, Gould KG, Taylor GP, Weber JN, and Bangham CR

Subjects
CD4 Lymphocyte Count, CD4-Positive T-Lymphocytes drug effects, Carrier State immunology, Enterotoxins pharmacology, Human T-lymphotropic virus 1 isolation & purification, Humans, In Vitro Techniques, Interferon-gamma biosynthesis, Lymphotoxin-alpha biosynthesis, Paraparesis, Tropical Spastic etiology, Proviruses immunology, Proviruses isolation & purification, Tetradecanoylphorbol Acetate pharmacology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes virology, Human T-lymphotropic virus 1 immunology, Interleukin-2 biosynthesis, Paraparesis, Tropical Spastic immunology, Tumor Necrosis Factor-alpha biosynthesis
Abstract

Significantly higher frequencies of tumor necrosis factor alpha- and interleukin-2-secreting human T-lymphotropic virus type 1 (HTLV-1)-specific CD4(+) T cells were present in the peripheral blood mononuclear cells of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients than in those of asymptomatic carriers with similar provirus loads. The data suggest that HTLV-1-specific CD4(+) T cells play a role in the pathogenesis of HAM/TSP.

Published
2003
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