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Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load.
Schuch, Anita; Salimi Alizei, Elahe; Heim, Kathrin; Wieland, Dominik; Kiraithe, Michael Muthamia; Kemming, Janine; Llewellyn-Lacey, Sian; Sogukpinar, Özlem; Ni, Yi; Urban, Stephan; Zimmermann, Peter; Nassal, Michael; Emmerich, Florian; Price, David A; Bengsch, Bertram; Luxenburger, Hendrik; Neumann-Haefelin, Christoph; Hofmann, Maike; Thimme, Robert.
Afiliação
  • Schuch A; Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
  • Salimi Alizei E; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Heim K; Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • Wieland D; Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
  • Kiraithe MM; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Kemming J; Faculty of Chemistry and Pharmacy, University of Freiburg, Freiburg, Germany.
  • Llewellyn-Lacey S; Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
  • Sogukpinar Ö; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Ni Y; Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • Urban S; Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
  • Zimmermann P; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Nassal M; Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
  • Emmerich F; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Price DA; Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
  • Bengsch B; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • Luxenburger H; Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • Neumann-Haefelin C; Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
  • Hofmann M; Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
  • Thimme R; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Gut ; 68(5): 905-915, 2019 05.
Article em En | MEDLINE | ID: mdl-30622109
OBJECTIVE: A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion. DESIGN: By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses. RESULTS: HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression. CONCLUSIONS: Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Produtos do Gene pol / Proteínas do Core Viral / Vírus da Hepatite B / Linfócitos T CD8-Positivos / Carga Viral / Hepatite B Crônica Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Gut Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Produtos do Gene pol / Proteínas do Core Viral / Vírus da Hepatite B / Linfócitos T CD8-Positivos / Carga Viral / Hepatite B Crônica Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Gut Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Reino Unido