van der Ploeg Esmee K, Golebski Korneliusz, van Nimwegen Menno, Fergusson Joannah R, Heesters Balthasar A, Martinez-Gonzalez Itziar, Kradolfer Chantal M A, van Tol Sophie, Scicluna Brendon P, de Bruijn Marjolein J W, de Boer Geertje M, Tramper-Stranders Gerdien A, Braunstahl Gert-Jan, van IJcken Wilfred F J, Nagtegaal A Paul, van Drunen Cornelis M, Fokkens Wytske J, Huylebroeck Danny, Spits Hergen, Hendriks Rudi W, Stadhouders Ralph, Bal Suzanne M
Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.
Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands.
Sci Immunol. 2021 Jan 29;6(55). doi: 10.1126/sciimmunol.abd3489.
Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO ILC2s are derived from resting CD45RA ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO ILC2s and mouse iILC2s. Frequencies of CD45RO inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.
第2组固有淋巴细胞（ILC2s）协调保护性2型免疫，并与多种免疫紊乱有关。在小鼠中，循环炎性ILC2s（iILC2s）被确定为2型细胞因子的主要来源。iILC2亚群在人类中的对应物仍然未知。在这里，我们鉴定出一种人类炎性ILC2群体，其存在于发炎的粘膜组织中，并以表面CD45RO表达为特异性标记。CD45RO ILC2s由静止的CD45RA ILC2s在受到上皮警报素如IL-33和TSLP激活后产生，这与STAT5激活以及IRF4/BATF转录因子的上调紧密相关。转录组分析揭示了人类CD45RO ILC2s与小鼠iILC2s之间存在显著相似性。在慢性鼻窦炎或哮喘患者的发炎粘膜组织和循环中，CD45RO炎性ILC2的频率增加，与疾病严重程度和对皮质类固醇治疗的抗性相关。皮质类固醇通过诱导向以低2型细胞因子和高双调蛋白表达为特征的免疫调节性ILC2表型分化，从而抑制CD45RA向CD45RO ILC2的转化。然而，一旦发生转化，CD45RO ILC2s对皮质类固醇具有抗性，这与代谢重编程相关，导致解毒途径的激活。我们的综合数据将CD45RO炎性ILC2s鉴定为与严重2型炎症性疾病和治疗抗性相关的小鼠iILC2s的人类类似物。
