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

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-restricte...

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Bibliographic Details
Published in:PloS one 2017-08, Vol.12 (8), p.e0182936-e0182936
Main Authors: Wisskirchen, Karin, Metzger, Kai, Schreiber, Sophia, Asen, Theresa, Weigand, Luise, Dargel, Christina, Witter, Klaus, Kieback, Elisa, Sprinzl, Martin F, Uckert, Wolfgang, Schiemann, Matthias, Busch, Dirk H, Krackhardt, Angela M, Protzer, Ulrike
Format: Article
Language:English
Subjects:
Antigens
Avidity
Biology and Life Sciences
Cancer
CD4 antigen
CD4-Positive T-Lymphocytes - immunology
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Cloning
Coculture Techniques
Cytokines
Deoxyribonucleic acid
DNA
Effector cells
Female
Focus groups
Gastroenterology
Genetic aspects
Genetic modification
Genotypes
Health aspects
Hepatitis
Hepatitis B
Hepatitis B - immunology
Hepatitis B Antigens - immunology
Hepatitis B virus
Hepatitis B virus - genetics
Hepatitis B virus - immunology
Hepatocellular carcinoma
Hepatoma
Histocompatibility antigen HLA
HLA-A2 Antigen - immunology
Humans
Immunity
Immunology
Infections
Interferon
Interleukin 2
Liver cancer
Lymphocytes
Lymphocytes B
Lymphocytes T
Major histocompatibility complex
Male
Medicine and Health Sciences
Middle Aged
Peptides
Physiological aspects
Physiology
Receptors
Receptors, Antigen, T-Cell - immunology
Receptors, Antigen, T-Cell - metabolism
Replication
Research and Analysis Methods
T cell antigen receptors
T cell receptors
T-cell receptor
Therapy
Tumor necrosis factor-α
Viral infections
Viral Proteins - metabolism
Virology
Viruses
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0182936