Plate IV.141 · Publications
A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection
Article in Nature, 10 July 2024.
Abstract
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.
Cite
@article{bosch2024liver,
title = {{A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection}},
author = {Bosch, Miriam and Kallin, Nina and Donakonda, Sainitin and Zhang, Jitao David and Wintersteller, Hannah and Hegenbarth, Silke and Heim, Kathrin and Ramirez, Carlos and Fürst, Anna and Lattouf, Elias Isaac and Feuerherd, Martin and Chattopadhyay, Sutirtha and Kumpesa, Nadine and Griesser, Vera and Hoflack, Jean-Christophe and Siebourg-Polster, Juliane and Mogler, Carolin and Swadling, Leo and Pallett, Laura J. and Meiser, Philippa and Manske, Katrin and de Almeida, Gustavo P. and Kosinska, Anna D. and Sandu, Ioana and Schneider, Annika and Steinbacher, Vincent and Teng, Yan and Schnabel, Julia and Theis, Fabian and Gehring, Adam J. and Boonstra, Andre and Janssen, Harry L. A. and Vandenbosch, Michiel and Cuypers, Eva and Öllinger, Rupert and Engleitner, Thomas and Rad, Roland and Steiger, Katja and Oxenius, Annette and Lo, Wan-Lin and Klepsch, Victoria and Baier, Gottfried and Holzmann, Bernhard and Maini, Mala K. and Heeren, Ron and Murray, Peter J. and Thimme, Robert and Herrmann, Carl and Protzer, Ulrike and Böttcher, Jan P. and Zehn, Dietmar and Wohlleber, Dirk and Lauer, Georg M. and Hofmann, Maike and Luangsay, Souphalone and Knolle, Percy A.},
journal = {Nature},
publisher = {Springer Science and Business Media LLC},
year = {2024},
month = jul,
doi = {10.1038/s41586-024-07630-7},
url = {https://doi.org/10.1038/s41586-024-07630-7},
pmid = {38987588},
pmcid = {PMC11269190}
}