Niehaus Christian, Klein Sebastian, Strunz Benedikt, Freyer Erich, Maasoumy Benjamin, Wedemeyer Heiner, Björkström Niklas K, Kraft Anke R M, Cornberg Markus
Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
Centre for Individualised Infection Medicine (CiiM), a joint venture between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany.
JHEP Rep. 2024 Mar 24;6(6):101074. doi: 10.1016/j.jhepr.2024.101074. eCollection 2024 Jun.
BACKGROUND & AIMS: Patients with advanced cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and may eventually lead to acute-on-chronic liver failure. One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. In this study, we analyzed the role of CD8 T cells in the ascites immune compartment.
Peripheral blood and ascites fluid were collected from 50 patients with decompensated cirrhosis. Phenotype and functional responses of CD8 T cells were analyzed, and obtained data were compared with each other as well as with healthy controls and patients with compensated cirrhosis.
High-dimensional flow cytometry revealed that CD8 T cells are abundant in the ascites of patients with cirrhosis and exhibit a chronically activated bystander phenotype with innate-like functions. Indeed, we identified distinct CXCR6CD69 clusters of late effector memory CD8 T cells that were rarely found in blood and correlated with clinical parameters of disease severity. Moreover, this CD8 T-cell population was hyperresponsive to innate cytokines and exhibited cytokine-mediated bystander activation. Interestingly, the Janus kinase (JAK) inhibitor tofacitinib was able to effectively block bystander-activated CXCR6CD69 CD8 T cells and significantly suppress effector molecule production.
The results indicate that CXCR6CD69 CD8 T cells in ascites are associated with disease severity and may contribute to inflammation in patients with decompensated cirrhosis, suggesting that targeted inhibition of this immune cell subset may be a viable therapeutic option.
Patients with advanced cirrhosis often develop hepatic decompensation, which is accompanied by systemic inflammation and eventually leads to acute-on-chronic liver failure. One important cause of systemic hyperinflammation is a dysregulated overshooting immune response in ascites in the abdominal cavity. In this study, we demonstrate that CXCR6CD69 CD8 T cells are abundant in the ascites of patients with cirrhosis, exhibit a chronically activated bystander phenotype, and correlate with clinical parameters of disease severity. Moreover, we show that the Janus kinase (JAK) inhibitor tofacitinib can effectively block these bystander-activated CXCR6CD69 CD8 T cells, suggesting that targeted inhibition of this immune cell subset may be a potential therapeutic strategy.
Prospective registry: INFEKTA (DRKS00010664).
晚期肝硬化患者常发生肝失代偿，伴有全身炎症，最终可能导致慢加急性肝衰竭。全身炎症反应过度的一个重要原因是腹腔腹水中免疫反应失调。在本研究中，我们分析了CD8 T细胞在腹水免疫微环境中的作用。
收集50例失代偿期肝硬化患者的外周血和腹水。分析CD8 T细胞的表型和功能反应，并将获得的数据相互比较，同时与健康对照者和代偿期肝硬化患者的数据进行比较。
高维流式细胞术显示，CD8 T细胞在肝硬化患者腹水中含量丰富，表现出具有固有样功能的慢性活化旁观者表型。事实上，我们鉴定出晚期效应记忆CD8 T细胞的不同CXCR6CD69簇，这些细胞在血液中很少见，且与疾病严重程度的临床参数相关。此外，这群CD8 T细胞对固有细胞因子反应过度，并表现出细胞因子介导的旁观者活化。有趣的是，Janus激酶（JAK）抑制剂托法替布能够有效阻断旁观者活化的CXCR6CD69 CD8 T细胞，并显著抑制效应分子的产生。
结果表明，腹水中的CXCR6CD69 CD8 T细胞与疾病严重程度相关，可能促成失代偿期肝硬化患者的炎症反应，提示靶向抑制这一免疫细胞亚群可能是一种可行的治疗选择。
晚期肝硬化患者常发生肝失代偿，伴有全身炎症，最终导致慢加急性肝衰竭。全身炎症反应过度的一个重要原因是腹腔腹水中免疫反应失调。在本研究中，我们证明CXCR6CD69 CD8 T细胞在肝硬化患者腹水中含量丰富，表现出慢性活化旁观者表型，并与疾病严重程度的临床参数相关。此外，我们表明Janus激酶（JAK）抑制剂托法替布可有效阻断这些旁观者活化的CXCR6CD69 CD8 T细胞，提示靶向抑制这一免疫细胞亚群可能是一种潜在的治疗策略。
前瞻性注册：INFEKTA（DRKS00010664）。
