TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection
Kathrin Heim 1 2 , Benedikt Binder 1 , Sagar 1 , Dominik Wieland 1 , Nina Hensel 1 2 , Sian Llewellyn-Lacey 3 , Emma Gostick 3 , David A Price 3 4 , Florian Emmerich 5 , Hildegard Vingerhoet 6 , Anke R M Kraft 7 8 , Markus Cornberg 8 9 , Tobias Boettler 1 , Christoph Neumann-Haefelin 1 , Dietmar Zehn 10 , Bertram Bengsch 1 11 , Maike Hofmann 12 , Robert Thimme 12
Affiliations
Affiliations
1
Internal Medicine II, Faculty of Medicine, Freiburg University Hospital, Freiburg, Germany.
2
Faculty of Biology, University of Freiburg, Freiburg, Germany.
3
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
4
Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK.
5
Institute for Transfusion Medicine and Gene Therapy, Factulty of Medicine, Freiburg University Hospital, Freiburg, Germany.
6
Internal Medicine II, Freiburg University Hospital, Freiburg, Germany.
7
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Niedersachsen, Germany.
8
German Centre for Infection Research Association, Braunschweig, Germany.
9
Department of Gastroenterology, Hepatology and Endocrinology, Centre for individualised Infection Medicine (CiiM), Hannover Medical School, Hannover, Germany.
10
Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.
11
Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany.
12
Internal Medicine II, Faculty of Medicine, Freiburg University Hospital, Freiburg, Germany [email protected][email protected].
PMID: 33097558 DOI: 10.1136/gutjnl-2020-322404
Abstract
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.
Keywords: T lymphocytes; chronic viral hepatitis; hepatitis B; immune response.