{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T12:17:07Z","timestamp":1793881027703,"version":"4.7.0"},"reference-count":90,"publisher":"Springer Science and Business Media LLC","issue":"8022","license":[{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2024,7,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Chronic hepatitis B virus (HBV) infection affects 300\u2009million patients worldwide\n                    <jats:sup>1,2<\/jats:sup>\n                    , in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes\n                    <jats:sup>3\u20137<\/jats:sup>\n                    . 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\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    CD8 T cells with enhanced\n                    <jats:italic>CREM<\/jats:italic>\n                    expression and transcriptional activity were detected at a frequency of 12\u201322% of HBV-specific CD8 T cells. Knocking out the inhibitory\n                    <jats:italic>CREM<\/jats:italic>\n                    \/\n                    <jats:italic>ICER<\/jats:italic>\n                    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\u2013PKA-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\u2013cAMP\u2013PKA 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\u2013cAMP\u2013PKA axis in an immune rheostat-like fashion.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-07630-7","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T12:01:55Z","timestamp":1720612915000},"page":"867-875","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":97,"title":["A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection"],"prefix":"10.1038","volume":"631","author":[{"given":"Miriam","family":"Bosch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Kallin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3216-8759","authenticated-orcid":false,"given":"Sainitin","family":"Donakonda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3085-0909","authenticated-orcid":false,"given":"Jitao 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