Division of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
J Autoimmun. 2010 Feb;34(1):1-6. doi: 10.1016/j.jaut.2009.08.008. Epub 2009 Aug 29.
The 'liver tolerance effect' mediates local and systemic tolerance to self and foreign antigens and has been attributed to specialized resident cells expressing anti-inflammatory mediators and inhibitory cell surface ligands for T cell activation. Non-parenchymal liver cells responsible for the tolerogenic properties of the liver are the resident dendritic cells (DCs), which comprise myeloid as well as plasmacytoid DCs, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs) as well as hepatic stellate cells (HSCs), also known as Ito cells. These cells mediate immunosuppression by production of anti-inflammatory cytokines such as IL-10 and TGFbeta as well as by expression of the negative co-stimulator for T cell activation programmed cell death ligand-1 (PD-L1). An interesting observation in this context is that knockout of IL-10 or PD-L1 (or the receptor PD-1) does not necessarily result in inflammatory liver damage whereas transgenic inhibition of TGFbeta signaling induces liver disease in mice resembling chronic cholangitis. However, depending on the mouse model and on the type of injury, e.g. autoimmune disease, allograft rejection or viral infection, IL-10 or TGFbeta and/or PD-1 as well as cytotoxic T lymphocyte antigen-4 (CTLA-4) contribute to the immunosuppressive mechanisms of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs), which seem to be converted in the liver from infiltrating conventional naïve CD4(+) T cells and/or effector CD4(+) T cells to control the disease. Finally, hepatocytes also contribute to the 'liver tolerance effect' by expression of MHC class II molecules, probably low levels of co-stimulatory molecules and high levels of the co-inhibitory molecule PD-L1.
“肝脏耐受效应”介导了对自身和外来抗原的局部和全身耐受，并归因于表达抗炎介质和抑制 T 细胞活化的细胞表面配体的特化驻留细胞。负责肝脏耐受特性的非实质细胞是驻留树突状细胞（DCs），包括髓样和浆细胞样 DCs、肝窦内皮细胞（LSECs）、枯否细胞（KCs）以及肝星状细胞（HSCs），也称为 Ito 细胞。这些细胞通过产生抗炎细胞因子（如 IL-10 和 TGFbeta）以及表达 T 细胞活化的负共刺激分子程序性细胞死亡配体-1（PD-L1）来介导免疫抑制。在这方面一个有趣的观察结果是，敲除 IL-10 或 PD-L1（或受体 PD-1）不一定导致炎症性肝损伤，而转基因抑制 TGFbeta 信号会导致类似于慢性胆管炎的小鼠肝脏疾病。然而，取决于小鼠模型和损伤类型，例如自身免疫性疾病、同种异体移植物排斥或病毒感染，IL-10 或 TGFbeta 和/或 PD-1 以及细胞毒性 T 淋巴细胞抗原-4（CTLA-4）有助于 CD4(+)CD25(+)Foxp3(+)调节性 T 细胞（Tregs）的免疫抑制机制，这些 Tregs 似乎是在肝脏中从浸润的常规幼稚 CD4(+)T 细胞和/或效应 CD4(+)T 细胞转化而来，以控制疾病。最后，肝细胞通过表达 MHC Ⅱ类分子、可能低水平的共刺激分子和高水平的共抑制分子 PD-L1 也有助于“肝脏耐受效应”。
