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

作者：Míriam Díez Bosch, Nina Kallin, Sainitin Donakonda, Jitao David Zhang, Hannah Wintersteller, Silke I. Hegenbarth, Kathrin Heim, Carlos Darío Ramírez, Anna Fürst, Elias Isaac Lattouf, Martin Feuerherd, Sutirtha Chattopadhyay, Nadine Kumpesa, Vera Griesser, Jean-Christophe Hoflack, Juliane Siebourg‐Polster, Carolin Mogler, Leo Swadling, Laura J. Pallett, Philippa Meiser, Katrin Manske, Gustavo Pereira de Almeida, Anna D. Kosinska, Ioana Sandu, Annika Schneider, Vincent Steinbacher, Yan Teng, Julia A. Schnabel, Fabian Joachim Theis, Adam J. Gehring, André Boonstra, Harry L.A. Janssen, Michiel Vandenbosch, Eva Cuypers, Rupert Öllinger, Thomas Engleitner, Roland Rad, Katja Steiger, Annette Oxenius, Wan‐Lin Lo, Victoria Klepsch, Gottfried Baier, Bernhard Holzmann, Mala K. Maini, Ron M. A. Heeren, Peter J. Murray, Robert Thimme, Carl Herrmann, Ulrike Protzer, Jan P. Böttcher, Dietmar Zehn, Dirk Wohlleber, Georg Michael Lauer, Maike Hofmann, Souphalone Luangsay, Percy Alexander Knolle · 发表于：Nature · 年份：2024 · DOI：10.1038/s41586-024-07630-7 · 被引用次数：94 · 研究领域：Hepatitis B Virus Studies、Diabetes and associated disorders、Immune Cell Function and Interaction

Abstract 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 recognizi...