Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load

• Verfasst von: Schuch, Anita [VerfasserIn]
• Verfasst von: Salimi Alizei, Elahe [VerfasserIn]
• Verfasst von: Heim, Kathrin [VerfasserIn]
• Verfasst von: Wieland, Dominik [VerfasserIn]
• Verfasst von: Kiraithe, Michael Muthamia [VerfasserIn]
• Verfasst von: Kemming, Janine [VerfasserIn]
• Verfasst von: Llewellyn-Lacey, Sian [VerfasserIn]
• Verfasst von: Sogukpinar, Özlem [VerfasserIn]
• Verfasst von: Ni, Yi [VerfasserIn]
• Verfasst von: Urban, Stephan [VerfasserIn]
• Verfasst von: Zimmermann, Peter [VerfasserIn]
• Verfasst von: Nassal, Michael [VerfasserIn]
• Verfasst von: Emmerich, Florian [VerfasserIn]
• Verfasst von: Price, David A. [VerfasserIn]
• Verfasst von: Bengsch, Bertram [VerfasserIn]
• Verfasst von: Luxenburger, Hendrik [VerfasserIn]
• Verfasst von: Neumann-Haefelin, Christoph [VerfasserIn]
• Verfasst von: Hofmann, Maike [VerfasserIn]
• Verfasst von: Thimme, Robert [VerfasserIn]
• Titel: Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load
• Verf.angabe: Anita Schuch, Elahe Salimi Alizei, Kathrin Heim, Dominik Wieland, Michael Muthamia Kiraithe, Janine Kemming, Sian Llewellyn-Lacey, Özlem Sogukpinar, Yi Ni, Stephan Urban, Peter Zimmermann, Michael Nassal, Florian Emmerich, David A. Price, Bertram Bengsch, Hendrik Luxenburger, Christoph Neumann-Haefelin, Maike Hofmann, Robert Thimme
• E-Jahr: 2019
• Jahr: 8 January 2019
• Umfang: 11 S.
• Fussnoten: Published Online First 8 January 2019 ; Gesehen am 03.03.2020
• Titel Quelle: Enthalten in: Gut
• Ort Quelle: London : BMJ Publishing Group, 1960
• Jahr Quelle: 2019
• Band/Heft Quelle: 68(2019), 5, Seite 905-915
• ISSN Quelle: 1468-3288
• DOI: doi:10.1136/gutjnl-2018-316641
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: BCL-2 family proteins
• Sach-SW: chronic viral hepatitis
• Sach-SW: hepatitis B
• Sach-SW: immune response
• Sach-SW: T lymphocytes
• K10plus-PPN: 1691443085

Abstract

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.