School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
J Hepatol. 2014 Jan;60(1):135-42. doi: 10.1016/j.jhep.2013.08.007. Epub 2013 Aug 19.
BACKGROUND & AIMS: Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141(+) subset, in healthy human liver and how this profile is altered in liver disease.
During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141(+) DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion.
Almost one third of liver CD11c(+) myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141(+) DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123(+) plasmacytoid DCs (pDCs) and CD1c(+) mDCs were expanded in diseased liver perfusates, CD141(+) DCs were significantly depleted. Despite their depletion, CD141(+) DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs.
Accumulation of CD141(+) DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity.
大量的肝脏免疫细胞可以检测到并响应由损伤、感染或恶性肿瘤引起的内稳态紊乱。树突状细胞（DC）是这些活动的核心，控制着耐受与免疫之间的平衡。我们对人类肝脏 DC 的大部分了解都来自于对肿瘤周围组织的研究。关于健康人肝脏中 DC 的表型和功能，特别是最近描述的 CD141（+）亚群，以及这种表型在肝脏疾病中是如何改变的，我们知之甚少。
在肝移植过程中，对健康供体和病变肝组织进行灌注，并分离肝单核细胞。通过流式细胞术检测肝脏灌流液中 DC 亚群的频率和表型，并通过混合淋巴细胞反应（MLR）和测量细胞因子分泌来评估 CD141（+）DC 的功能。
与循环 mDC 相比，近三分之一的肝脏 CD11c（+）髓样 DC（mDC）表达 CD141，而 <5%的循环 mDC 表达 CD141。肝 CD141（+）DC 在同种异体 MLR 中表现出促炎功能，诱导 T 细胞产生干扰素γ（IFN-γ）和白细胞介素（IL）-17。虽然 CD123（+）浆细胞样 DC（pDC）和 CD1c（+）mDC 在病变肝灌流液中扩增，但 CD141（+）DC 明显耗竭。尽管耗竭，来自病变肝的 CD141（+）DC 产生的多聚（I：C）诱导的 IFN lambda（IFN-λ）明显高于供体 DC。
健康肝脏中 CD141（+）DC 的积累，在肝脏疾病中明显耗竭，提示 mDC 亚群在肝脏免疫中存在差异参与。
