Forkel Marianne, Berglin Lena, Kekäläinen Eliisa, Carlsson Adrian, Svedin Emma, Michaëlsson Jakob, Nagasawa Maho, Erjefält Jonas S, Mori Michiko, Flodström-Tullberg Malin, Bergquist Annika, Ljunggren Hans-Gustaf, Westgren Magnus, Lindforss Ulrik, Friberg Danielle, Jorns Carl, Ellis Ewa, Björkström Niklas K, Mjösberg Jenny
Center for Infectious Medicine, Department of Medicine, Karolinska Institute Stockholm, Sweden.
Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands.
Eur J Immunol. 2017 Aug;47(8):1280-1294. doi: 10.1002/eji.201646890. Epub 2017 Jul 11.
Human innate lymphoid cells have been described to exist in different organs, with functional deregulation of these cells contributing to several disease states. Here, we performed the first detailed characterization of the phenotype, tissue-residency properties, and functionality of ILC1s, ILC2s, and ILC3s in the human adult and fetal liver. In addition, we investigated changes in the ILC compartment in liver fibrosis. A unique composition of tissue-resident ILCs was observed in nonfibrotic livers as compared with that in mucosal tissues, with NKp44 ILC3s accounting for the majority of total intrahepatic ILCs. The frequency of ILC2s, representing a small fraction of ILCs in nonfibrotic livers, increased in liver fibrosis and correlated directly with the severity of the disease. Notably, intrahepatic ILC2s secreted the profibrotic cytokine IL-13 when exposed to IL-33 and thymic stromal lymphopoetin (TSLP); these cytokines were produced by hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells in response to TLR-3 stimulation. In summary, the present results provide the first detailed characterization of intrahepatic ILCs in human adult and fetal liver. The results indicate a role for ILC2s in human liver fibrosis, implying that targeting ILC2s might be a novel therapeutic strategy for its treatment.
人类天然淋巴细胞已被描述存在于不同器官中，这些细胞的功能失调会导致多种疾病状态。在此，我们首次对人类成人和胎儿肝脏中的1型天然淋巴细胞（ILC1s）、2型天然淋巴细胞（ILC2s）和3型天然淋巴细胞（ILC3s）的表型、组织驻留特性及功能进行了详细表征。此外，我们还研究了肝纤维化过程中天然淋巴细胞区室的变化。与黏膜组织相比，在非纤维化肝脏中观察到了独特的组织驻留天然淋巴细胞组成，其中自然杀伤细胞蛋白44阳性的ILC3s占肝内天然淋巴细胞总数的大部分。在非纤维化肝脏中占天然淋巴细胞一小部分的ILC2s频率在肝纤维化过程中增加，且与疾病严重程度直接相关。值得注意的是，肝内ILC2s在暴露于白细胞介素-33（IL-33）和胸腺基质淋巴细胞生成素（TSLP）时会分泌促纤维化细胞因子白细胞介素-13；这些细胞因子由肝细胞、肝星状细胞（HSCs）和库普弗细胞在Toll样受体-3（TLR-3）刺激下产生。总之，本研究结果首次对人类成人和胎儿肝脏中的肝内天然淋巴细胞进行了详细表征。结果表明ILC2s在人类肝纤维化中发挥作用，这意味着靶向ILC2s可能是一种治疗肝纤维化的新型策略。
