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

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      CD4-Positive T-Lymphocytes/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Hepatitis B virus/*immunology ; Receptors, Antigen, T-Cell/*immunology; Coculture Techniques ; Female ; HLA-A2 Antigen/immunology ; Hepatitis B/immunology ; Hepatitis B Antigens/immunology ; Hepatitis B virus/genetics ; Humans ; Male ; Middle Aged ; Receptors, Antigen, T-Cell/metabolism ; Viral Proteins/metabolism
    • 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.
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    • Accession Number:
      0 (HLA-A*02 antigen)
      0 (HLA-A2 Antigen)
      0 (Hepatitis B Antigens)
      0 (Receptors, Antigen, T-Cell)
      0 (Viral Proteins)
    • Publication Date:
      Date Created: 20170810 Date Completed: 20171003 Latest Revision: 20200306
    • Publication Date:
      20240105
    • Accession Number:
      PMC5549754
    • Accession Number:
      10.1371/journal.pone.0182936
    • Accession Number:
      28792537