Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Cell Mol Gastroenterol Hepatol. 2024;17(1):79-91. doi: 10.1016/j.jcmgh.2023.09.006. Epub 2023 Sep 19.
BACKGROUND & AIMS: The liver has a distinct capacity to induce immune tolerance to hepatic antigens. Although liver tolerance can be advantageous for preventing autoimmune and inflammatory diseases, it also can 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 C-reactive protein (CRP)-myelin basic protein (MBP) mice expressing the neuroantigen MBP in hepatocytes, providing profound resistance to MBP-induced neuroinflammation. Tolerance induction was studied after transfer of MBP-specific CD4 T cells into CRP-MBP mice, and tolerance mechanisms were tested using depleting or blocking antibodies.
Although tolerant CRP-MBP mice display increased numbers of forkhead box P3+ regulatory T cells, we here found them not essential for the maintenance of hepatic tolerance. Instead, upon MBP recognition in the liver, MBP-specific T cells became activated to produce interferon (IFN)γ, which, in turn, induced local up-regulation of recruitment molecules, including Chemokine (C-X-C motif) ligand9 and its receptor C-X-C motif chemokine receptor3, 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 interleukin 10-producing type 1 regulatory T cells, and significantly up-regulated the expression of immune checkpoint molecules, notably cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Intriguingly, although liver tolerance was not affected by impairment of interleukin 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.
肝脏具有诱导对肝抗原产生免疫耐受的独特能力。虽然肝脏耐受有利于预防自身免疫和炎症性疾病，但它也可能通过防止感染或恶性细胞的免疫监视而产生不利影响。在这里，我们研究了建立肝脏耐受的免疫机制。
在 CRP-髓鞘碱性蛋白（MBP）小鼠中研究了耐受，这些小鼠在肝细胞中表达神经抗原 MBP，对 MBP 诱导的神经炎症具有明显的抗性。在将 MBP 特异性 CD4 T 细胞转移到 CRP-MBP 小鼠后，研究了耐受诱导，并使用耗竭或阻断抗体测试了耐受机制。
尽管耐受的 CRP-MBP 小鼠显示出增加的叉头框 P3+调节性 T 细胞数量，但我们在这里发现它们对于维持肝脏耐受不是必需的。相反，在肝脏中识别 MBP 后，MBP 特异性 T 细胞被激活以产生干扰素（IFN）γ，反过来又诱导局部募集分子的上调，包括趋化因子（C-X-C 基序）配体 9 和其受体 C-X-C 基序趋化因子受体 3，促进内皮细胞易位和将 MBP 特异性 T 细胞重新定向到肝实质。在那里，易位的 MBP 特异性 CD4 T 细胞部分转化为产生白细胞介素 10 的 1 型调节性 T 细胞，并显著上调免疫检查点分子的表达，特别是细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）。有趣的是，尽管白细胞介素 10 信号的损害不影响肝脏耐受，但同时阻断 IFNγ和 CTLA-4 会破坏 MBP 的肝脏耐受诱导，导致这些小鼠发生神经炎症自身免疫性疾病。
IFNγ介导的自身反应性 CD4 T 细胞向肝脏的重定向和检查点分子（包括 CTLA-4）的上调对于肝脏耐受的诱导是必要的，因此代表了增强或预防肝脏耐受的潜在治疗靶标。
