학술논문
Building and Optimizing a Virus-specific T Cell Receptor Library for Targeted Immunotherapy in Viral Infections.
Document Type
Article
Author
Source
Subject
*T cell receptors
*IMMUNOTHERAPY
*VIRAL disease treatment
*TOLL-like receptors
*EPSTEIN-Barr virus
*HUMAN cytomegalovirus
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Language
ISSN
2045-2322
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-gamma1 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. [ABSTRACT FROM AUTHOR]