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Sci Rep. 2014 Feb 25;4:4166. doi: 10.1038/srep04166.

Building and optimizing a virus-specific T cell receptor library for targeted immunotherapy in viral infections.

Author information

1
Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*Star), Singapore.
2
Departments of Microbiology and Biological Sciences, Immunology Programme, National University of Singapore, Singapore.
3
1] Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*Star), Singapore [2] Program of Emerging Viral Diseases, Duke-NUS Graduate Medical School, National University of Singapore, Singapore.
4
1] Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*Star), Singapore [2] Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA [3] Saint Louis University Liver Center, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.

Abstract

Restoration of antigen-specific T cell immunity has the potential to clear persistent viral infection. T cell receptor (TCR) gene therapy can reconstitute CD8 T cell immunity in chronic patients. We cloned 10 virus-specific TCRs targeting 5 different viruses, causing chronic and acute infection. All 10 TCR genetic constructs were optimized for expression using a P2A sequence, codon optimization and the addition of a non-native disulfide bond. However, maximum TCR expression was only achieved after establishing the optimal orientation of the alpha and beta chains in the expression cassette; 9/10 TCRs favored the beta-P2A-alpha orientation over alpha-P2A-beta. Optimal TCR expression was associated with a significant increase in the frequency of IFN-gamma+ T cells. In addition, activating cells for transduction in the presence of Toll-like receptor ligands further enhanced IFN-gamma production. Thus, we have built a virus-specific TCR library that has potential for therapeutic intervention in chronic viral infection or virus-related cancers.

PMID:
24566718
PMCID:
PMC3933865
DOI:
10.1038/srep04166
[Indexed for MEDLINE]
Free PMC Article

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