Background and Aims: 24-NorUrsodeoxycholic acid (NorUDCA) is novel therapy for immune-mediated liver diseases such as primary sclerosing cholangitis (PSC) where dysregulated T cells including CD8+ T cells cause liver immunopathology. We hypothesized that NorUDCA may directly modulate CD8+ T cell effector function thus contributing to its therapeutic efficacy independent of anti-cholestatic effects. Methods: NorUDCA effects on CD8+ T cell function in vivo were investigated in a hepatic injury model system induced by excessive CD8+ T cell immune response upon non-cytolytic lymphocytic choriomeningitis virus (LCMV) infection. Mechanistic studies included molecular and biochemical approaches, flow cytometry and metabolic assays in mouse CD8+ T cells in vitro. Mass spectrometry (MS) was used to identify potential targets modulated by NorUDCA in CD8+ T cells. NorUDCA signaling effects observed in murine systems were validated in peripheral T cells from healthy volunteers and PSC patients. Results: In vivo NorUDCA ameliorated hepatic injury and systemic inflammation upon LCMV infection. Mechanistically, NorUDCA demonstrated a strong immunomodulatory efficacy in CD8+ T cells affecting lymphoblastogenesis, mTORC1 signaling and glycolysis of CD8+ T cells. With MS, we identified that NorUDCA regulates CD8+ T cells via targeting mTORC1. NorUDCA's impact on mTORC1 signaling was further confirmed in circulating human CD8+ T cells. Conclusions: NorUDCA possesses a yet-unrecognized direct modulatory potency on CD8+ T cells and attenuates excessive CD8+ T cell hepatic immunopathology. These findings may be relevant for treatment of immune-mediated liver diseases such as PSC and beyond.

中文翻译：

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24-Nor-熊去氧胆酸重塑CD8 + T细胞的免疫代谢并减轻肝炎

背景与目的：24-去甲熊去氧胆酸（NorUDCA）是针对免疫介导的肝脏疾病（例如原发性硬化性胆管炎（PSC））的新型疗法，其中CD8 + T细胞等失调的T细胞引起肝脏免疫病理学改变。我们假设NorUDCA可以直接调节CD8 + T细胞效应子的功能，从而有助于其治疗功效而与抗胆汁淤积作用无关。方法：在非细胞溶解性淋巴细胞性脉络膜脑膜炎病毒（LCMV）感染引起的过量CD8 + T细胞免疫应答的肝损伤模型系统中，研究了NorUDCA对体内CD8 + T细胞功能的影响。机制研究包括分子和生化方法，流式细胞仪和小鼠CD8 + T细胞体外代谢测定。质谱（MS）用于鉴定NorUDCA在CD8 + T细胞中调控的潜在靶标。在健康志愿者和PSC患者的外周血T细胞中验证了在鼠类系统中观察到的NorUDCA信号传导效应。结果：体内NorUDCA改善了LCMV感染后的肝损伤和全身炎症。从机理上讲，NorUDCA在CD8 + T细胞中具有很强的免疫调节功效，可影响淋巴母细胞生成，mTORC1信号传导和CD8 + T细胞的糖酵解。对于MS，我们确定了NorUDCA通过靶向mTORC1调节CD8 + T细胞。在循环的人CD8 + T细胞中，进一步证实了NorUDCA对mTORC1信号的影响。结论：NorUDCA对CD8 + T细胞具有尚未被认可的直接调节能力，并减轻了过量的CD8 + T细胞的肝免疫病理学。