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

• 成果类型: Article
• 署名作者: Bosch, Miriam; Kallin, Nina; Donakonda, Sainitin; Zhang, Jitao David; Wintersteller, Hannah; Hegenbarth, Silke; Heim, Kathrin; Ramirez, Carlos; Fuerst, Anna; Lattouf, Elias Isaac; Feuerherd, Martin; Chattopadhyay, Sutirtha; Kumpesa, Nadine; Griesser, Vera; Hoflack, Jean-Christophe; Siebourg-Polster, Juliane; Mogler, Carolin; Swadling, Leo; Pallett, Laura J.; Meiser, Philippa; Manske, Katrin; de Almeida, Gustavo P.; Kosinska, Anna D.; Sandu, Ioana; Schneider, Annika; Steinbacher, Vincent; Teng, Yan; Schnabel, Julia; Theis, Fabian; Gehring, Adam J.; Boonstra, Andre; Janssen, Harry L. A.; Vandenbosch, Michiel; Cuypers, Eva; Oellinger, Rupert; Engleitner, Thomas; Rad, Roland; Steiger, Katja; Oxenius, Annette; Lo, Wan-Lin; Klepsch, Victoria; Baier, Gottfried; Holzmann, Bernhard; Maini, Mala K.; Heeren, Ron; Murray, Peter J.; Thimme, Robert; Herrmann, Carl; Protzer, Ulrike; Boettcher, Jan P.; Zehn, Dietmar; Wohlleber, Dirk; Lauer, Georg M.; Hofmann, Maike; Luangsay, Souphalone; Knolle, Percy A.
• 署名单位: Technical University of Munich; Roche Holding; University of Freiburg; Ruprecht Karls University Heidelberg; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Technical University of Munich; University of London; University College London; Technical University of Munich; Technical University of Munich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; German Center for Infection Research; Swiss Federal Institutes of Technology Domain; ETH Zurich; Helmholtz Association; Helmholtz-Center Munich - German Research Center for Environmental Health; Technical University of Munich; University of Toronto; University Health Network Toronto; Toronto General Hospital; University of Toronto; Erasmus University Rotterdam; Erasmus MC; University of Toronto; University Health Network Toronto; Toronto General Hospital; Maastricht University; Technical University of Munich; Technical University of Munich; Utah System of Higher Education; University of Utah; Medical University of Innsbruck; Technical University of Munich; Max Planck Society; Technical University of Munich
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6260
• DOI: 10.1038/s41586-024-07630-7
• 发表日期: 2024-07-25
• 页码: 867-+
• 关键词: cyclic adenosine-monophosphate; b-virus infection; rna-seq; adenovirus vectors; endothelial-cells; hepatitis; antigen; expression; binding; genome

摘要

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.