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TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection

Heim, Kathrin, Binder, Benedikt, Sagar, Wieland, Dominik, Hensel, Nina, Llewellyn-Lacey, Sian, Gostick, Emma, Price, David A. ORCID:, Emmerich, Florian, Vingerhoet, Hildegard, Kraft, Anke R M, Cornberg, Markus, Boettler, Tobias, Neumann-Haefelin, Christoph, Zehn, Dietmar, Bengsch, Bertram, Hofmann, Maike and Thimme, Robert 2021. TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection. Gut 70 , pp. 1550-1560. 10.1136/gutjnl-2020-322404

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Objective Chronic hepatitis B virus (HBV) infection is characterised by HBV-specific CD8+ T cell dysfunction that has been linked to Tcell exhaustion, a distinct differentiation programme associated with persisting antigen recognition. Recently, Thymocyte Selection-Associated High Mobility Group Box (TOX) was identified as master regulator of CD8+ T cell exhaustion. Here, we addressed the role of TOX in HBV-specific CD8+ T cell dysfunction associated with different clinical phases of infection. Design We investigated TOX expression in HBV-specific CD8+ T cells from 53 HLA-A*01:01, HLA-A*11:01 and HLA-A*02:01 positive patients from different HBV infection phases and compared it to hepatitis C virus (HCV)-specific, cytomegalovirus (CMV)-specific, Epstein-Barr virus (EBV)-specific and influenza virus (FLU)-specific CD8+ T cells. Phenotypic and functional analyses of virus-specific CD8+ T cells were performed after peptide-loaded tetramer-enrichment and peptide-specific expansion. Results Our results show that TOX expression in HBV-specific CD8+ T cells is linked to chronic antigen stimulation, correlates with viral load and is associated with phenotypic and functional characteristics of T-cell exhaustion. In contrast, similar TOX expression in EBV-specific and CMV-specific CD8+ T cells is not linked to T-cell dysfunction suggesting different underlying programmes. TOX expression in HBV-specific CD8+ T cells is also affected by targeted antigens, for example, core versus polymerase. In HBV-specific CD8+ T cells, TOX expression is maintained after spontaneous or therapy-mediated viral control in chronic but not self-limiting acute HBV infection indicating a permanent molecular imprint after chronic but not temporary stimulation. Conclusion Our data highlight TOX as biomarker specific for dysfunctional virus-specific CD8+ T cells in the context of an actively persisting infection.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: BMJ Publishing Group
ISSN: 0017-5749
Date of First Compliant Deposit: 5 November 2020
Date of Acceptance: 24 September 2020
Last Modified: 05 May 2023 00:02

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