Fibrosis contributes to tissue repair, but excessive fibrosis disrupts organ function. Alagille syndrome (ALGS, caused by mutations in JAGGED1) results in liver disease and characteristic fibrosis. Here, we show that Jag1Ndr/Ndr mice, a model for ALGS, recapitulate ALGS-like fibrosis. Single-cell RNA-seq and multi-color flow cytometry of the liver revealed immature hepatocytes and paradoxically low intrahepatic T cell infiltration despite cholestasis in Jag1Ndr/Ndr mice. Thymic and splenic regulatory T cells (Tregs) were enriched and Jag1Ndr/Ndr lymphocyte immune and fibrotic capacity was tested with adoptive transfer into Rag1-/- mice, challenged with dextran sulfate sodium (DSS) or bile duct ligation (BDL). Transplanted Jag1Ndr/Ndr lymphocytes were less inflammatory with fewer activated T cells than Jag1+/+ lymphocytes in response to DSS. Cholestasis induced by BDL in Rag1-/- mice with Jag1Ndr/Ndr lymphocytes resulted in periportal Treg accumulation and three-fold less periportal fibrosis than in Rag1-/- mice with Jag1+/+ lymphocytes. Finally, the Jag1Ndr/Ndr hepatocyte expression profile and Treg overrepresentation were corroborated in patients' liver samples. Jag1-dependent hepatic and immune defects thus interact to determine the fibrotic process in ALGS.

中文翻译：

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Jag1 不足通过 T 细胞和肝细胞分化缺陷改变肝纤维化。


纤维化有助于组织修复，但过度纤维化会破坏器官功能。Alagille 综合征 （ALGS，由 JAGGED1 突变引起）导致肝病和特征性纤维化。在这里，我们展示了 Jag1Ndr/Ndr 小鼠（ALGS 模型）概括了 ALGS 样纤维化。肝脏的单细胞 RNA-seq 和多色流式细胞术显示，尽管 Jag1Ndr/Ndr 小鼠存在胆汁淤积，但肝内 T 细胞浸润水平较低。富集胸腺和脾调节性 T 细胞 （Tregs），并通过过继转移到 Rag1-/- 小鼠中，用葡聚糖硫酸钠 （DSS） 或胆管结扎术 （BDL） 攻击来测试 Jag1Ndr/Ndr 淋巴细胞免疫和纤维化能力。与 Jag1 + / + 淋巴细胞相比，移植的 Jag1Ndr/Ndr 淋巴细胞对 DSS 的炎症性较低，活化的 T 细胞较少。BDL 诱导的具有 Jag1Ndr/Ndr 淋巴细胞的 Rag1-/- 小鼠的胆汁淤积导致门静脉周围 Treg 积累，并且门静脉周围纤维化比具有 Jag1 +/+ 淋巴细胞的 Rag1-/- 小鼠少三倍。最后，在患者的肝脏样本中证实了 Jag1Ndr/Ndr 肝细胞表达谱和 Treg 过代表。因此，Jag1 依赖性肝脏和免疫缺陷相互作用以确定 ALGS 中的纤维化过程。