Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Hamburg, Germany.
Front Immunol. 2019 May 28;10:1065. doi: 10.3389/fimmu.2019.01065. eCollection 2019.
Natural Killer T (NKT) cells are CD1d-restricted innate-like T cells that can rapidly release stored cytokines upon recognition of lipid antigens. In mice, type I NKT cells seem to promote liver inflammation, whereas type II NKT cells seem to restrict hepatitis. Here, we aimed at characterizing the role of human type I and type II NKT in patients with autoimmune hepatitis (AIH). NKT cells were analyzed by flow cytometry in peripheral blood and liver of AIH patients and control groups. α-galactosylceramide-loaded or sulfatide-loaded tetramers were used to detect type I or II NKT cells, respectively. Hepatic CD1d was stained by -hybridization of liver biopsies. Type II NKT cells were more prevalent in human peripheral blood and liver than type I NKT cells. In AIH patients, the frequency of sulfatide-reactive type II NKT cells was significantly increased in peripheral blood (0.11% of peripheral blood leukocytes) and liver (3.78% of intrahepatic leukocytes) compared to healthy individuals (0.05% and 1.82%) and patients with drug-induced liver injury (0.06% and 2.03%; < 0.05). Intrahepatic type II NKT cells of AIH patients had a different cytokine profile than healthy subjects with an increased frequency of TNFα (77.8% vs. 59.1%, < 0.05), decreased IFNγ (32.7% vs. 63.0%, < 0.05) and a complete lack of IL-4 expressing cells (0% vs. 2.1%, < 0.05). T cells in portal tracts expressed significantly more CD1d-RNA in AIH livers compared to controls. This study supports that in contrast to their assumed protective role in mice, human intrahepatic, sulfatide-reactive type II NKT cells displayed a proinflammatory cytokine profile in patients with AIH. Infiltrating T cells in portal areas of AIH patients overexpressed CD1d and could thereby activate type II NKT cells.
自然杀伤 T（NKT）细胞是 CD1d 限制性先天样 T 细胞，在识别脂质抗原后可以迅速释放储存的细胞因子。在小鼠中，I 型 NKT 细胞似乎促进肝脏炎症，而 II 型 NKT 细胞似乎限制肝炎。在这里，我们旨在表征人类 I 型和 II 型 NKT 在自身免疫性肝炎（AIH）患者中的作用。 通过流式细胞术分析 AIH 患者和对照组的外周血和肝中的 NKT 细胞。使用α-半乳糖神经酰胺负载或硫酸酯负载四聚体分别检测 I 型或 II 型 NKT 细胞。通过肝活检的β-杂交染色检测肝 CD1d。 II 型 NKT 细胞在人类外周血和肝脏中的流行率高于 I 型 NKT 细胞。与健康个体（0.05%和 1.82%）和药物性肝损伤患者（0.06%和 2.03%）相比，AIH 患者外周血（外周血白细胞的 0.11%）和肝脏（肝内白细胞的 3.78%）中硫酸酯反应性 II 型 NKT 细胞的频率显着增加（<0.05）。与健康个体相比，AIH 患者的肝内 II 型 NKT 细胞具有不同的细胞因子谱，TNFα的频率增加（77.8%比 59.1%，<0.05），IFNγ减少（32.7%比 63.0%，<0.05），并且完全缺乏表达 IL-4 的细胞（0%比 2.1%，<0.05）。与对照组相比，AIH 肝脏中的门脉区 T 细胞表达明显更多的 CD1d-RNA。这项研究支持与在小鼠中假定的保护作用相反，人类肝内、硫酸酯反应性 II 型 NKT 细胞在 AIH 患者中表现出促炎细胞因子谱。AIH 患者门脉区的浸润 T 细胞过度表达 CD1d，从而可以激活 II 型 NKT 细胞。
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