A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.