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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

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 inf...

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Main Authors: Schuch, Anita (Author) , Salimi Alizei, Elahe (Author) , Heim, Kathrin (Author) , Wieland, Dominik (Author) , Kiraithe, Michael Muthamia (Author) , Kemming, Janine (Author) , Llewellyn-Lacey, Sian (Author) , Sogukpinar, Özlem (Author) , Ni, Yi (Author) , Urban, Stephan (Author) , Zimmermann, Peter (Author) , Nassal, Michael (Author) , Emmerich, Florian (Author) , Price, David A. (Author) , Bengsch, Bertram (Author) , Luxenburger, Hendrik (Author) , Neumann-Haefelin, Christoph (Author) , Hofmann, Maike (Author) , Thimme, Robert (Author)
Format: Article (Journal)
Language:English
Published: 8 January 2019
In: Gut
Year: 2019, Volume: 68, Issue: 5, Pages: 905-915
ISSN:1468-3288
DOI:10.1136/gutjnl-2018-316641
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/gutjnl-2018-316641
Verlag, lizenzpflichtig: https://gut.bmj.com/content/68/5/905
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Author Notes: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
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Summary: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.
Item Description:Published Online First 8 January 2019
Gesehen am 03.03.2020
Physical Description:Online Resource
ISSN:1468-3288
DOI:10.1136/gutjnl-2018-316641

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