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Codon Optimization of the Human Papillomavirus E7 Oncogene Induces a CD8(+) T Cell Response to a Cryptic Epitope Not Harbored by Wild-Type E7

Codon optimization of nucleotide sequences is a widely used method to achieve high levels of transgene expression for basic and clinical research. Until now, immunological side effects have not been described. To trigger T cell responses against human papillomavirus, we incubated T cells with dendri...

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Autores principales: Lorenz, Felix K. M., Wilde, Susanne, Voigt, Katrin, Kieback, Elisa, Mosetter, Barbara, Schendel, Dolores J., Uckert, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370481/
https://www.ncbi.nlm.nih.gov/pubmed/25799237
http://dx.doi.org/10.1371/journal.pone.0121633
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author Lorenz, Felix K. M.
Wilde, Susanne
Voigt, Katrin
Kieback, Elisa
Mosetter, Barbara
Schendel, Dolores J.
Uckert, Wolfgang
author_facet Lorenz, Felix K. M.
Wilde, Susanne
Voigt, Katrin
Kieback, Elisa
Mosetter, Barbara
Schendel, Dolores J.
Uckert, Wolfgang
author_sort Lorenz, Felix K. M.
collection PubMed
description Codon optimization of nucleotide sequences is a widely used method to achieve high levels of transgene expression for basic and clinical research. Until now, immunological side effects have not been described. To trigger T cell responses against human papillomavirus, we incubated T cells with dendritic cells that were pulsed with RNA encoding the codon-optimized E7 oncogene. All T cell receptors isolated from responding T cell clones recognized target cells expressing the codon-optimized E7 gene but not the wild type E7 sequence. Epitope mapping revealed recognition of a cryptic epitope from the +3 alternative reading frame of codon-optimized E7, which is not encoded by the wild type E7 sequence. The introduction of a stop codon into the +3 alternative reading frame protected the transgene product from recognition by T cell receptor gene-modified T cells. This is the first experimental study demonstrating that codon optimization can render a transgene artificially immunogenic through generation of a dominant cryptic epitope. This finding may be of great importance for the clinical field of gene therapy to avoid rejection of gene-corrected cells and for the design of DNA- and RNA-based vaccines, where codon optimization may artificially add a strong immunogenic component to the vaccine.
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spelling pubmed-43704812015-04-04 Codon Optimization of the Human Papillomavirus E7 Oncogene Induces a CD8(+) T Cell Response to a Cryptic Epitope Not Harbored by Wild-Type E7 Lorenz, Felix K. M. Wilde, Susanne Voigt, Katrin Kieback, Elisa Mosetter, Barbara Schendel, Dolores J. Uckert, Wolfgang PLoS One Research Article Codon optimization of nucleotide sequences is a widely used method to achieve high levels of transgene expression for basic and clinical research. Until now, immunological side effects have not been described. To trigger T cell responses against human papillomavirus, we incubated T cells with dendritic cells that were pulsed with RNA encoding the codon-optimized E7 oncogene. All T cell receptors isolated from responding T cell clones recognized target cells expressing the codon-optimized E7 gene but not the wild type E7 sequence. Epitope mapping revealed recognition of a cryptic epitope from the +3 alternative reading frame of codon-optimized E7, which is not encoded by the wild type E7 sequence. The introduction of a stop codon into the +3 alternative reading frame protected the transgene product from recognition by T cell receptor gene-modified T cells. This is the first experimental study demonstrating that codon optimization can render a transgene artificially immunogenic through generation of a dominant cryptic epitope. This finding may be of great importance for the clinical field of gene therapy to avoid rejection of gene-corrected cells and for the design of DNA- and RNA-based vaccines, where codon optimization may artificially add a strong immunogenic component to the vaccine. Public Library of Science 2015-03-23 /pmc/articles/PMC4370481/ /pubmed/25799237 http://dx.doi.org/10.1371/journal.pone.0121633 Text en © 2015 Lorenz et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lorenz, Felix K. M.
Wilde, Susanne
Voigt, Katrin
Kieback, Elisa
Mosetter, Barbara
Schendel, Dolores J.
Uckert, Wolfgang
Codon Optimization of the Human Papillomavirus E7 Oncogene Induces a CD8(+) T Cell Response to a Cryptic Epitope Not Harbored by Wild-Type E7
title Codon Optimization of the Human Papillomavirus E7 Oncogene Induces a CD8(+) T Cell Response to a Cryptic Epitope Not Harbored by Wild-Type E7
title_full Codon Optimization of the Human Papillomavirus E7 Oncogene Induces a CD8(+) T Cell Response to a Cryptic Epitope Not Harbored by Wild-Type E7
title_fullStr Codon Optimization of the Human Papillomavirus E7 Oncogene Induces a CD8(+) T Cell Response to a Cryptic Epitope Not Harbored by Wild-Type E7
title_full_unstemmed Codon Optimization of the Human Papillomavirus E7 Oncogene Induces a CD8(+) T Cell Response to a Cryptic Epitope Not Harbored by Wild-Type E7
title_short Codon Optimization of the Human Papillomavirus E7 Oncogene Induces a CD8(+) T Cell Response to a Cryptic Epitope Not Harbored by Wild-Type E7
title_sort codon optimization of the human papillomavirus e7 oncogene induces a cd8(+) t cell response to a cryptic epitope not harbored by wild-type e7
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370481/
https://www.ncbi.nlm.nih.gov/pubmed/25799237
http://dx.doi.org/10.1371/journal.pone.0121633
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