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PLoS One. 2015 Mar 23;10(3):e0121633. doi: 10.1371/journal.pone.0121633. eCollection 2015.

Codon optimization of the human papillomavirus E7 oncogene induces a CD8+ T cell response to a cryptic epitope not harbored by wild-type E7.

Author information

1
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
2
Institute for Molecular Immunology, Helmholtz-Zentrum München, Munich, Germany.
3
Institute of Biology, Humboldt University, Berlin, Germany.
4
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Institute of Biology, Humboldt University, Berlin, Germany.

Abstract

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.

PMID:
25799237
PMCID:
PMC4370481
DOI:
10.1371/journal.pone.0121633
[Indexed for MEDLINE]
Free PMC Article

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