肝脏具有诱导免疫耐受性应对肝脏抗原的独特能力。尽管肝脏耐受性对于预防自身免疫性和炎症性疾病可能有利，但它也可能通过阻止对感染或恶性细胞的免疫监视而造成损害。本研究调查了建立肝脏耐受性的免疫机制。通过在肝细胞中表达神经抗原髓鞘基本蛋白（MBP）来研究CRP-MBP小鼠中的耐受性，在CRP-MBP小鼠中转移MBP特异性CD4 T细胞（tg4）来研究耐受性诱导，并使用耗竭或阻断抗体来测试耐受性机制。尽管具有耐受性的CRP-MBP小鼠显示FOXP3+调节性T细胞数量增加，但我们发现它们对于维持肝脏耐受性不是必需的。相反，在肝脏中MBP识别后，MBP特异性T细胞被激活产生IFNγ，进而诱导招募分子（包括CXCL9及其受体CXCR3）的局部上调，促进内皮细胞跨位移和MBP特异性T细胞重新定向进入肝实质内。通过转位的MBP特异性CD4 T细胞部分转化为产生IL-10的Tr1细胞，并显著上调免疫检查点分子，特别是CTLA-4的表达。有趣的是，虽然IL-10信号的障碍不影响肝脏耐受性，但IFNγ和CTLA-4的同时阻断消除了肝脏对MBP的耐受诱导，导致这些小鼠出现神经炎症性自身免疫疾病。IFNγ介导的自反应CD4 T细胞重新定位到肝脏，以及免疫检查点分子，包括CTLA-4的上调，对于肝脏耐受性诱导至关重要，因此代表了潜在的提高或预防肝脏耐受性的治疗靶点。 版权所有 2023 年 作者。由 Elsevier 公司出版。保留所有权利。

The liver has a distinct capacity to induce immune tolerance to hepatic antigens. Whereas liver tolerance can be advantageous for preventing autoimmune and inflammatory diseases, it can also be detrimental by preventing immune surveillance of infected or malignant cells. Here, we investigated the immune mechanisms that establish hepatic tolerance.Tolerance was investigated in CRP-MBP mice expressing the neuroantigen myelin basic protein (MBP) in hepatocytes, providing profound resistance to MBP-induced neuroinflammation. Tolerance-induction was studied following transfer of MBP-specific CD4 T cells (tg4) into CRP-MBP mice, and tolerance mechanisms were tested using depleting or blocking antibodies.Although tolerant CRP-MBP mice display increased numbers of FOXP3+ Tregs, we here find them not essential for the maintenance of hepatic tolerance. Instead, upon MBP-recognition in the liver, MBP-specific T cells became activated to produce IFNγ, which, in turn, induced local up-regulation of recruitment molecules, including CXCL9 and its receptor CXCR3, facilitating endothelial translocation and redirection of MBP-specific T cells into the hepatic parenchyma. There, the translocated MBP-specific CD4 T cells partly converted into IL-10 producing Tr1 cells, and significantly up-regulated the expression of immune checkpoint molecules, notably CTLA-4. Intriguingly, whereas liver tolerance was not affected by impairment of IL-10 signaling, concomitant blockade of IFNγ and CTLA-4 abrogated hepatic tolerance induction to MBP resulting in neuroinflammatory autoimmune disease in these mice.IFNγ-mediated redirection of autoreactive CD4 T cells into the liver and up-regulation of checkpoint molecules, including CTLA-4 were essential for tolerance induction in the liver, hence representing a potential treatment target for boosting or preventing liver tolerance.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.