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Isolation and functional characterization of hepatitis B virus-specific T-cell receptors as new tools for experimental and clinical use

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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. and Metzger, K. and Schreiber, S. and Asen, T. and Weigand, L. and Dargel, C. and Witter, K. and Kieback, E. and Sprinzl, M.F. and Uckert, W. and Schiemann, M. and Busch, D.H. and 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
Publisher:Public Library of Science
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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