A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection
Authors: Bosch Miriam , Kallin Nina , Donakonda Sainitin , Zhang Jitao David , Wintersteller Hannah , Hegenbarth Silke , Heim Kathrin , Ramirez Carlos , Fürst 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 , Öllinger 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 , Böttcher Jan P. , Zehn Dietmar , Wohlleber Dirk , Lauer Georg M. , Hofmann Maike , Luangsay Souphalone , Knolle Percy A. 
Published: July 2024

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.