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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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Hauptverfasser: Schuch, Anita (VerfasserIn) , Salimi Alizei, Elahe (VerfasserIn) , Heim, Kathrin (VerfasserIn) , Wieland, Dominik (VerfasserIn) , Kiraithe, Michael Muthamia (VerfasserIn) , Kemming, Janine (VerfasserIn) , Llewellyn-Lacey, Sian (VerfasserIn) , Sogukpinar, Özlem (VerfasserIn) , Ni, Yi (VerfasserIn) , Urban, Stephan (VerfasserIn) , Zimmermann, Peter (VerfasserIn) , Nassal, Michael (VerfasserIn) , Emmerich, Florian (VerfasserIn) , Price, David A. (VerfasserIn) , Bengsch, Bertram (VerfasserIn) , Luxenburger, Hendrik (VerfasserIn) , Neumann-Haefelin, Christoph (VerfasserIn) , Hofmann, Maike (VerfasserIn) , Thimme, Robert (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 8 January 2019
In: Gut
Year: 2019, Jahrgang: 68, Heft: 5, Pages: 905-915
ISSN:1468-3288
DOI:10.1136/gutjnl-2018-316641
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1136/gutjnl-2018-316641
Verlag, lizenzpflichtig: https://gut.bmj.com/content/68/5/905
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Published Online First 8 January 2019
Gesehen am 03.03.2020
Beschreibung:Online Resource
ISSN:1468-3288
DOI:10.1136/gutjnl-2018-316641

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