Immunodominance of Adenovirus-Derived CD8+T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization
Schoene D, Hrycak CP, Windmann S, Lapuente D, Dittmer U, Tenbusch M, Bayer W (2017)
Publication Type: Journal article
Publication year: 2017
Journal
Book Volume: 91
Journal Issue: 20
DOI: 10.1128/JVI.01184-17
Abstract
Adenovirus (Ad)-based immunization is a popular approach in vaccine development, and Ad-based vectors are renowned for their potential to induce strong CD8+T cell responses to the encoded transgene. Surprisingly, we previously found in the mouse Friend retrovirus (FV) model that Ad-based immunization did not induce CD8+T cell responses to the FV Leader-Gag-derived immunodominant epitope GagL85-93We show now that induction of GagL85-93-specific CD8+T cells was highly effective when leader-Gag was delivered by plasmid DNA immunization, implying a role for Ad-derived epitopes in mediating unresponsiveness. By immunizing with DNA constructs encoding strings of GagL85-93and the two Ad-derived epitopes DNA-binding protein418-426(DBP418-426) and hexon486-494, we confirmed that Ad epitopes prevent induction of GagL85-93-specific CD8+T cells. Interestingly, while DBP418-426did not interfere with GagL85-93-specific CD8+T cell induction, the H-2Dd-restricted hexon486-494suppressed the CD8+T cell response to the H-2Db-restricted GagL85-93strongly in H-2b/dmice but not in H-2b/bmice. This finding indicates that competition occurs at the level of responding CD8+T cells, and we could indeed demonstrate that coimmunization with an interleukin 2 (IL-2)-encoding plasmid restored GagL85-93-specific CD8+T cell responses to epitope strings in the presence of hexon486-494IL-2 codelivery did not restore GagL85-93responsiveness in Ad-based immunization, however, likely due to the presence of further epitopes in the Ad vector. Our findings show that seemingly immunodominant transgene epitopes can be dominated by Ad-derived epitopes. These findings underline the importance of thorough characterization of vaccine vectors, and modifications of vectors or immunogens may be required to prevent impaired transgene-specific immune responses.IMPORTANCEAd-based vectors are widely used in experimental preclinical and clinical immunization studies against numerous infectious agents, such as human immunodeficiency virus, Ebola virus,Plasmodium falciparum, orMycobacterium tuberculosisPreexisting immunity to Ad-based vectors is widely recognized as a hindrance to the widespread use of Ad-based vectors for immunizations in humans; however, our data show that an immune response to Ad-derived T cell epitopes can also result in loss or impairment of transgene-specific immune responses in prenaive vaccinees due to immune competition. Our results highlight that seemingly immunodominant epitopes may be affected by dominance of vector-derived epitopes, and modifications of the vector design or the immunogens employed in immunization may lead to more effective vaccines.
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Germany (DE)How to cite
APA:
Schoene, D., Hrycak, C.P., Windmann, S., Lapuente, D., Dittmer, U., Tenbusch, M., & Bayer, W. (2017). Immunodominance of Adenovirus-Derived CD8+T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization. Journal of Virology, 91(20). https://doi.org/10.1128/JVI.01184-17
MLA:
Schoene, Dominik, et al. "Immunodominance of Adenovirus-Derived CD8+T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization." Journal of Virology 91.20 (2017).
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