A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection PMID: 38987588

Target-related Cytokines

2026-09-23

A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection

Nature. 2024 Jul;631(8022):867-875. doi: 10.1038/s41586-024-07630-7.

Miriam Bosch ^# ¹ , Nina Kallin ^# ¹ , Sainitin Donakonda ¹ , Jitao David Zhang ² , Hannah Wintersteller ¹ , Silke Hegenbarth ¹ , Kathrin Heim ³ , Carlos Ramirez ⁴ , Anna Fürst ¹ , Elias Isaac Lattouf ⁵ , Martin Feuerherd ⁵ , Sutirtha Chattopadhyay ¹ , Nadine Kumpesa ² , Vera Griesser ² , Jean-Christophe Hoflack ² , Juliane Siebourg-Polster ² , Carolin Mogler ⁶ , Leo Swadling ⁷ , Laura J Pallett ⁷ , Philippa Meiser ¹ , Katrin Manske ¹ , Gustavo P de Almeida ⁸ , Anna D Kosinska ⁹ ¹⁰ ¹¹ , Ioana Sandu ¹² , Annika Schneider ¹ , Vincent Steinbacher ¹ , Yan Teng ⁹ , Julia Schnabel ¹³ , Fabian Theis ¹⁴ , Adam J Gehring ¹⁵ ¹⁶ , Andre Boonstra ¹⁷ , Harry L A Janssen ¹⁷ ¹⁸ , Michiel Vandenbosch ¹⁹ , Eva Cuypers ¹⁹ , Rupert Öllinger ²⁰ , Thomas Engleitner ²⁰ , Roland Rad ²⁰ , Katja Steiger ²¹ , Annette Oxenius ¹² , Wan-Lin Lo ²² , Victoria Klepsch ²³ , Gottfried Baier ²³ , Bernhard Holzmann ²⁴ , Mala K Maini ⁶ , Ron Heeren ¹⁹ , Peter J Murray ²⁵ , Robert Thimme ³ , Carl Herrmann ⁴ ⁵ , Ulrike Protzer ⁸ ⁹ ¹⁰ , Jan P Böttcher ¹ , Dietmar Zehn ⁸ , Dirk Wohlleber ¹ , Georg M Lauer ⁵ , Maike Hofmann ³ , Souphalone Luangsay ² , Percy A Knolle ²⁶ ²⁷ ²⁸

Affiliations

1. Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany.
2. Roche Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Basel, Basel, Switzerland.
3. Third Department of Medicine, University Hospital Freiburg, Freiburg, Germany.
4. Health Data Science Unit, Biomedical Genomics Group, Bioquant, Faculty of Medicine Heidelberg, Heidelberg, Germany.
5. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
6. Institute of Pathology, School of Medicine and Health, TUM, Munich, Germany.
7. Division of Infection and Immunity, Institute of Immunity and Transplantation, University College London, London, UK.
8. Institute of Immunology and Animal Physiology, School of Life Science, TUM, Munich, Germany.
9. Institute of Virology, School of Medicine and Health, TUM, Munich, Germany.
10. Helmholtz Zentrum München, Munich, Germany.
11. German Center for Infection Research, Munich site, Munich, Germany.
12. Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
13. Institute of Machine Learning and Biomedical Imaging, Helmholtz Zentrum Munich, Munich, Germany.
14. Institute of Computational Biology, TUM, Munich, Germany.
15. Toronto Centre for Liver Disease and Toronto General Hospital Research Institute, Toronto, Ontario, Canada.
16. Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
17. Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
18. Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
19. Institute of Multimodal Imaging, University of Maastricht, Maastricht, The Netherlands.
20. Institute of Molecular Oncology and Functional Genomics, School of Medicine and Health, TUM, Munich, Germany.
21. Comparative Experimental Pathology, School of Medicine and Health, TUM, Munich, Germany.
22. Department of Pathology, University of Utah, Salt Lake City, UT, USA.
23. Institute of Cell Genetics, Medical University of Innsbruck, Innsbruck, Austria.
24. Department of Surgery, School of Medicine and Health, TUM, Munich, Germany.
25. Max Planck Institute of Biochemistry, Martinsried, Munich, Germany.
26. Institute of Molecular Immunology, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany. [email protected].
27. German Center for Infection Research, Munich site, Munich, Germany. [email protected].
28. Institute of Molecular Immunology, School of Life Science, TUM, Munich, Germany. [email protected].
# Contributed equally.

Abstract

Chronic hepatitis B virus (HBV) Infection affects 300 million patients worldwide^1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes^3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent Infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6⁺ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6⁺ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic Infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling Kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral Antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.