德国慕尼黑工业大学Percy A. Knolle团队近期取得重要工作进展，他们研究提出，肝脏免疫“变阻器”调节慢性HBV感染中的CD8 T细胞免疫。相关研究成果2024年7月10日在线发表于《自然》杂志上。

据介绍，慢性乙型肝炎病毒（HBV）感染影响全球3亿患者，其中病毒特异性CD8 T细胞通过尚不明确的机制失去功能，无法消除HBV感染的肝细胞。

研究人员证明了肝脏免疫“变阻器”使病毒特异性CD8 T细胞对激活无效，并导致其效应器功能的丧失。在HBV等嗜肝病毒持续感染的临床前模型中，功能失调的病毒特异性CXCR6⁺ CD8 T细胞在肝脏中积聚，作为特征性标志，显示出与T细胞耗竭不同的cAMP反应元件调节剂（CREM）的转录活性增强。在慢性乙型肝炎患者中，检测到循环和肝内HBV特异性CXCR6⁺ CD8 T细胞具有增强的CREM表达和转录活性，其频率为HBV特异性CD8 T细胞的12-22%。然而，敲除T细胞中的抑制性CREM/ICER亚型未能挽救T细胞免疫。这表明CREM活性是T细胞功能丧失的结果，而不是原因，CREM上游蛋白激酶a（PKA）磷酸化增强的观察进一步支持了这一点。

研究人员发现，在持续性肝感染中，T细胞腺苷酸环化酶活性的增加增强了cAMP-PKA信号传导，从而增强了CREM活性，抑制了T细胞活化和效应器功能。从机制上讲，识别肝细胞上抗原的CD8 T细胞与肝窦内皮细胞建立了密切和广泛的接触，从而增强了T细胞中的腺苷酸环化酶-cAMP-PKA信号传导。在这些识别肝细胞抗原的肝CD8 T细胞中，T细胞受体信号通路的关键信号激酶的磷酸化受损，使其对激活不敏感。

因此，与肝窦内皮细胞的密切接触会抑制HBV特异性CD8 T细胞的激活和效应器功能，这些细胞通过腺苷酸环化酶-cAMP-PKA轴，以免疫“变阻器”样的方式靶向表达病毒抗原的肝细胞。

附：英文原文

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

Author: Bosch, Miriam, Kallin, Nina, Donakonda, Sainitin, Zhang, Jitao David, Wintersteller, Hannah, Hegenbarth, Silke, Heim, Kathrin, Ramirez, Carlos, Frst, 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, llinger, 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, Bttcher, Jan P., Zehn, Dietmar, Wohlleber, Dirk, Lauer, Georg M., Hofmann, Maike, Luangsay, Souphalone, Knolle, Percy A.

Issue&Volume: 2024-07-10

Abstract: Chronic hepatitis B virus (HBV) infection affects 300million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3,4,5,6,7. 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.

DOI: 10.1038/s41586-024-07630-7

Source: https://www.nature.com/articles/s41586-024-07630-7