Binding of TCR multimers and a TCR-like antibody with distinct fine-specificities is dependent on the surface density of HLA complexes

Class I Major Histocompatibility Complex (MHC) molecules evolved to sample degraded protein fragments from the interior of the cell, and to display them at the surface for immune surveillance by CD8+ T cells. The ability of these lymphocytes to identify immunogenic peptide-MHC (pMHC) products on, fo...

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Main Authors: Low, Jianrong L., Gehring, Adam J., Kranz, David M., Grotenbreg, Gijsbert M., Yau, Yin Hoe, Shochat, Susana Geifman, Bertoletti, Antonio, Naidoo, Anneta, Yeo, Gladys, Ho, Zi Zong
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2013
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Online Access:https://hdl.handle.net/10356/98967
http://hdl.handle.net/10220/10919
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spelling sg-ntu-dr.10356-989672023-02-28T17:04:32Z Binding of TCR multimers and a TCR-like antibody with distinct fine-specificities is dependent on the surface density of HLA complexes Low, Jianrong L. Gehring, Adam J. Kranz, David M. Grotenbreg, Gijsbert M. Yau, Yin Hoe Shochat, Susana Geifman Bertoletti, Antonio Naidoo, Anneta Yeo, Gladys Ho, Zi Zong School of Biological Sciences DRNTU::Science::Biological sciences Class I Major Histocompatibility Complex (MHC) molecules evolved to sample degraded protein fragments from the interior of the cell, and to display them at the surface for immune surveillance by CD8+ T cells. The ability of these lymphocytes to identify immunogenic peptide-MHC (pMHC) products on, for example, infected hepatocytes, and to subsequently eliminate those cells, is crucial for the control of hepatitis B virus (HBV). Various protein scaffolds have been designed to recapitulate the specific recognition of presented antigens with the aim to be exploited both diagnostically (e.g. to visualize cells exposed to infectious agents or cellular transformation) and therapeutically (e.g. for the delivery of drugs to compromised cells). In line with this, we report the construction of a soluble tetrameric form of an αβ T cell receptor (TCR) specific for the HBV epitope Env183–191 restricted by HLA-A*02:01, and compare its avidity and fine-specificity with a TCR-like monoclonal antibody generated against the same HLA target. A flow cytometry-based assay with streptavidin-coated beads loaded with Env183–191/HLA-A*02:01 complexes at high surface density, enabled us to probe the specific interaction of these molecules with their cognate pMHC. We demonstrate that the TCR tetramer has similar avidity for the pMHC as the antibody, but they differ in their fine-specificity, with only the TCR tetramer being capable of binding both natural variants of the Env183–191 epitope found in HBV genotypes A/C/D (187Arg) and genotype B (187Lys). Collectively, the results highlight the promiscuity of our soluble TCR, which could be an advantageous feature when targeting cells infected with a mutation-prone virus, but that binding of the soluble oligomeric TCR relies considerably on the surface density of the presented antigen. Published version 2013-07-04T02:06:05Z 2019-12-06T20:01:39Z 2013-07-04T02:06:05Z 2019-12-06T20:01:39Z 2012 2012 Journal Article Low, J. L., Naidoo, A., Yeo, G., Gehring, A. J., Ho, Z. Z., Yau, Y. H., et al. (2012). Binding of TCR Multimers and a TCR-Like Antibody with Distinct Fine-Specificities Is Dependent on the Surface Density of HLA Complexes. PLoS ONE, 7(12), e51397. 1932-6203 https://hdl.handle.net/10356/98967 http://hdl.handle.net/10220/10919 10.1371/journal.pone.0051397 23251518 en PLoS ONE © 2012 The Authors. This paper was published in PLoS ONE and is made available as an electronic reprint (preprint) with permission of The Authors. The paper can be found at the following official DOI: [http://dx.doi.org/10.1371/journal.pone.0051397]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences
spellingShingle DRNTU::Science::Biological sciences
Low, Jianrong L.
Gehring, Adam J.
Kranz, David M.
Grotenbreg, Gijsbert M.
Yau, Yin Hoe
Shochat, Susana Geifman
Bertoletti, Antonio
Naidoo, Anneta
Yeo, Gladys
Ho, Zi Zong
Binding of TCR multimers and a TCR-like antibody with distinct fine-specificities is dependent on the surface density of HLA complexes
description Class I Major Histocompatibility Complex (MHC) molecules evolved to sample degraded protein fragments from the interior of the cell, and to display them at the surface for immune surveillance by CD8+ T cells. The ability of these lymphocytes to identify immunogenic peptide-MHC (pMHC) products on, for example, infected hepatocytes, and to subsequently eliminate those cells, is crucial for the control of hepatitis B virus (HBV). Various protein scaffolds have been designed to recapitulate the specific recognition of presented antigens with the aim to be exploited both diagnostically (e.g. to visualize cells exposed to infectious agents or cellular transformation) and therapeutically (e.g. for the delivery of drugs to compromised cells). In line with this, we report the construction of a soluble tetrameric form of an αβ T cell receptor (TCR) specific for the HBV epitope Env183–191 restricted by HLA-A*02:01, and compare its avidity and fine-specificity with a TCR-like monoclonal antibody generated against the same HLA target. A flow cytometry-based assay with streptavidin-coated beads loaded with Env183–191/HLA-A*02:01 complexes at high surface density, enabled us to probe the specific interaction of these molecules with their cognate pMHC. We demonstrate that the TCR tetramer has similar avidity for the pMHC as the antibody, but they differ in their fine-specificity, with only the TCR tetramer being capable of binding both natural variants of the Env183–191 epitope found in HBV genotypes A/C/D (187Arg) and genotype B (187Lys). Collectively, the results highlight the promiscuity of our soluble TCR, which could be an advantageous feature when targeting cells infected with a mutation-prone virus, but that binding of the soluble oligomeric TCR relies considerably on the surface density of the presented antigen.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Low, Jianrong L.
Gehring, Adam J.
Kranz, David M.
Grotenbreg, Gijsbert M.
Yau, Yin Hoe
Shochat, Susana Geifman
Bertoletti, Antonio
Naidoo, Anneta
Yeo, Gladys
Ho, Zi Zong
format Article
author Low, Jianrong L.
Gehring, Adam J.
Kranz, David M.
Grotenbreg, Gijsbert M.
Yau, Yin Hoe
Shochat, Susana Geifman
Bertoletti, Antonio
Naidoo, Anneta
Yeo, Gladys
Ho, Zi Zong
author_sort Low, Jianrong L.
title Binding of TCR multimers and a TCR-like antibody with distinct fine-specificities is dependent on the surface density of HLA complexes
title_short Binding of TCR multimers and a TCR-like antibody with distinct fine-specificities is dependent on the surface density of HLA complexes
title_full Binding of TCR multimers and a TCR-like antibody with distinct fine-specificities is dependent on the surface density of HLA complexes
title_fullStr Binding of TCR multimers and a TCR-like antibody with distinct fine-specificities is dependent on the surface density of HLA complexes
title_full_unstemmed Binding of TCR multimers and a TCR-like antibody with distinct fine-specificities is dependent on the surface density of HLA complexes
title_sort binding of tcr multimers and a tcr-like antibody with distinct fine-specificities is dependent on the surface density of hla complexes
publishDate 2013
url https://hdl.handle.net/10356/98967
http://hdl.handle.net/10220/10919
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