PT - JOURNAL ARTICLE AU - Kathrin Heim AU - Benedikt Binder AU - Sagar AU - Dominik Wieland AU - Nina Hensel AU - Sian Llewellyn-Lacey AU - Emma Gostick AU - David A. Price AU - Florian Emmerich AU - Hildegard Vingerhoet AU - Anke R M Kraft AU - Markus Cornberg AU - Tobias Boettler AU - Christoph Neumann-Haefelin AU - Dietmar Zehn AU - Bertram Bengsch AU - Maike Hofmann AU - Robert Thimme TI - TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection AID - 10.1136/gutjnl-2020-322404 DP - 2021 Aug 01 TA - Gut PG - 1550--1560 VI - 70 IP - 8 4099 - http://gut.bmj.com/content/70/8/1550.short 4100 - http://gut.bmj.com/content/70/8/1550.full SO - Gut2021 Aug 01; 70 AB - 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.All data relevant to the study are included in the article or uploaded as online supplemental information.