Bamboat Zubin M, Stableford Jennifer A, Plitas George, Burt Bryan M, Nguyen Hoang M, Welles Alexander P, Gonen Mithat, Young James W, DeMatteo Ronald P
Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
J Immunol. 2009 Feb 15;182(4):1901-11. doi: 10.4049/jimmunol.0803404.
The liver is believed to promote tolerance, which may be beneficial due to its constant exposure to foreign Ags from the portal circulation. Although dendritic cells (DCs) are critical mediators of immune responses, little is known about human liver DCs. We compared freshly purified liver DCs from surgical specimens with autologous blood DCs. Liver and blood DCs were equally immature, but had distinct subset compositions. BDCA-1(+) DCs represented the most prevalent liver DC subset, whereas the majority of peripheral blood DCs were CD16(+). Upon TLR4 ligation, blood DCs secreted multiple proinflammatory cytokines, whereas liver DCs produced substantial amounts of IL-10. Liver DCs induced less proliferation of allogeneic T cells both in a primary MLR and after restimulation. Similarly, Ag-specific CD4(+) T cells were less responsive to restimulation when initially stimulated by autologous liver DCs rather than blood DCs. In addition, liver DCs generated more suppressive CD4(+)CD25(+)FoxP3(+) T regulatory cells and IL-4-producing Th2 cells via an IL-10-dependent mechanism. Our findings are critical to understanding hepatic immunity and demonstrate that human liver DCs promote immunologic hyporesponsiveness that may contribute to hepatic tolerance.
肝脏被认为可促进免疫耐受，鉴于其持续暴露于来自门静脉循环的外来抗原，这可能是有益的。尽管树突状细胞（DCs）是免疫反应的关键介质，但对人肝脏DCs却知之甚少。我们将手术标本中新鲜纯化的肝脏DCs与自体血液DCs进行了比较。肝脏和血液DCs同样未成熟，但具有不同的亚群组成。BDCA-1(+) DCs是最主要的肝脏DC亚群，而外周血DCs大多数为CD16(+)。经Toll样受体4（TLR4）连接后，血液DCs分泌多种促炎细胞因子，而肝脏DCs产生大量白细胞介素-10（IL-10）。在初次混合淋巴细胞反应（MLR）及再次刺激后，肝脏DCs诱导的同种异体T细胞增殖较少。同样，当抗原特异性CD4(+) T细胞最初由自体肝脏DCs而非血液DCs刺激时，对再次刺激的反应性较低。此外，肝脏DCs通过IL-10依赖机制产生更多抑制性CD4(+)CD25(+)FoxP3(+)调节性T细胞和产生IL-4的辅助性T2（Th2）细胞。我们这些发现对于理解肝脏免疫至关重要，并表明人肝脏DCs促进免疫低反应性，这可能有助于肝脏耐受。
