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| Item Type: | Article |
|---|---|
| Title: | Isolation and functional characterization of hepatitis B virus-specific T-cell receptors as new tools for experimental and clinical use |
| Creators Name: | Wisskirchen, K., Metzger, K., Schreiber, S., Asen, T., Weigand, L., Dargel, C., Witter, K., Kieback, E., Sprinzl, M.F., Uckert, W., Schiemann, M., Busch, D.H., Krackhardt, A.M. and Protzer, U. |
| Abstract: | T-cell therapy of chronic hepatitis B is a novel approach to restore antiviral T-cell immunity and cure the infection. We aimed at identifying T-cell receptors (TCR) with high functional avidity that have the potential to be used for adoptive T-cell therapy. To this end, we cloned HLA-A*02-restricted, hepatitis B virus (HBV)-specific T cells from patients with acute or resolved HBV infection. We isolated 11 envelope- or core-specific TCRs and evaluated them in comprehensive functional analyses. T cells were genetically modified by retroviral transduction to express HBV-specific TCRs. CD8+ as well as CD4+ T cells became effector T cells recognizing even picomolar concentrations of cognate peptide. TCR-transduced T cells were polyfunctional, secreting the cytokines interferon gamma, tumor necrosis factor alpha and interleukin-2, and effectively killed hepatoma cells replicating HBV. Notably, our collection of HBV-specific TCRs recognized peptides derived from HBV genotypes A, B, C and D presented on different HLA-A*02 subtypes common in areas with high HBV prevalence. When co-cultured with HBV-infected cells, TCR-transduced T cells rapidly reduced viral markers within two days. Our unique set of HBV-specific TCRs with different affinities represents an interesting tool for elucidating mechanisms of TCR-MHC interaction and dissecting specific anti-HBV mechanisms exerted by T cells. TCRs with high functional avidity might be suited to redirect T cells for adoptive T-cell therapy of chronic hepatitis B and HBV-induced hepatocellular carcinoma. |
| Keywords: | CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, HLA-A2 Antigen, Hepatitis B, Hepatitis B Antigens, Hepatitis B virus, Receptors, Antigen, T-Cell, Viral Proteins |
| Source: | PLoS ONE |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Volume: | 12 |
| Number: | 8 |
| Page Range: | e0182936 |
| Date: | 8 August 2017 |
| Official Publication: | https://doi.org/10.1371/journal.pone.0182936 |
| PubMed: | View item in PubMed |
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