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A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.
Nature 631, 867–875 (2024)
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DOI
PMC
Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. 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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Cyclic Adenosine-monophosphate; B-virus Infection; Rna-seq; Adenovirus Vectors; Endothelial-cells; Hepatitis; Antigen; Expression; Binding; Activation
ISSN (print) / ISBN
0028-0836
e-ISSN
1476-4687
Zeitschrift
Nature
Quellenangaben
Band: 631,
Seiten: 867–875
Verlag
Nature Publishing Group
Verlagsort
London
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Virology (VIRO)
Institute for Machine Learning in Biomed Imaging (IML)
Institute for Machine Learning in Biomed Imaging (IML)
Förderungen
Swiss National Science Foundation (SNSF)
Institute of Pathology, School of Medicine and Health at TUM
Deutsche Forschungsgemeinschaft (DFG)
DFG
EU
ERC AG
DFG Heisenberg programme
Janssen Pharma
Institute of Pathology, School of Medicine and Health at TUM
Deutsche Forschungsgemeinschaft (DFG)
DFG
EU
ERC AG
DFG Heisenberg programme
Janssen Pharma