Harmon Cathal, Robinson Mark W, Fahey Ronan, Whelan Sarah, Houlihan Diarmaid D, Geoghegan Justin, O'Farrelly Cliona
School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Liver Unit, St. Vincent's University Hospital, Dublin, Ireland.
Eur J Immunol. 2016 Sep;46(9):2111-20. doi: 10.1002/eji.201646559.
The adult human liver is enriched with natural killer (NK) cells, accounting for 30-50% of hepatic lymphocytes, which include tissue-resident hepatic NK-cell subpopulations, distinct from peripheral blood NK cells. In murine liver, a subset of liver-resident hepatic NK cells have altered expression of the two highly related T-box transcription factors, T-bet and eomesodermin (Eomes). Here, we investigate the heterogeneity of T-bet and Eomes expression in NK cells from healthy adult human liver with a view to identifying human liver-resident populations. Hepatic NK cells were isolated from donor liver perfusates and biopsies obtained during orthotopic liver transplantation (N = 28). Hepatic CD56(bright) NK cells were Eomes(hi) T-bet(lo) , a phenotype virtually absent from peripheral blood. These NK cells express the chemokine receptor CXCR6 (chemokine (C-X-C motif) receptor 6), a marker of tissue residency, which is absent from hepatic CD56(dim) and blood NK cells. Compared to blood populations, these hepatic CD56(bright) NK cells have increased expression of activatory receptors (NKp44, NKp46, and NKG2D). They show reduced ability to produce IFN-γ but enhanced degranulation in response to challenge with target cells. This functionally distinct population of hepatic NK cells constitutes 20-30% of the total hepatic lymphocyte repertoire and represents a tissue-resident immune cell population adapted to the tolerogenic liver microenvironment.
成人肝脏富含自然杀伤（NK）细胞，占肝淋巴细胞的30 - 50%，其中包括组织驻留性肝NK细胞亚群，与外周血NK细胞不同。在小鼠肝脏中，一部分驻留性肝NK细胞中两个高度相关的T盒转录因子T-bet和中胚层因子（Eomes）的表达发生了改变。在此，我们研究健康成人肝脏NK细胞中T-bet和Eomes表达的异质性，以识别肝脏驻留细胞群。从原位肝移植期间获得的供体肝脏灌注液和活检组织中分离出肝NK细胞（N = 28）。肝CD56（明亮）NK细胞为Eomes（高表达）T-bet（低表达），这是外周血中几乎不存在的一种表型。这些NK细胞表达趋化因子受体CXCR6（趋化因子（C-X-C基序）受体6），这是组织驻留的一个标志物，肝CD56（暗淡）和血液NK细胞中不存在该标志物。与血液中的细胞群相比，这些肝CD56（明亮）NK细胞的激活受体（NKp44、NKp46和NKG2D）表达增加。它们产生IFN-γ的能力降低，但在受到靶细胞攻击时脱颗粒增强。这种功能上不同的肝NK细胞群占肝淋巴细胞总数的20 - 30%，代表了一种适应肝脏致耐受性微环境的组织驻留免疫细胞群。
