Research ArticleASTHMA

Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases

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Science Immunology  29 Jan 2021:
Vol. 6, Issue 55, eabd3489
DOI: 10.1126/sciimmunol.abd3489

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Defiant ILC2s resist steroids

Group 2 innate lymphoid cells (ILC2s) contribute to the inflammation associated with human allergic airway diseases, including asthma and chronic rhinosinusitis. Corticosteroid drugs are used to manage type 2 respiratory diseases, but steroid resistance may arise in the course of therapy. By comparing ILC2s from inflamed nasal polyps with blood ILC2s from healthy controls, van der Ploeg et al. observed that enhanced cytokine expression by nasal polyp ILC2s and loss of steroid responsiveness were both associated with ILC2s becoming CD45RO+ rather than CD45RA+ like most resting ILC2s. Expression of the CD45RO isoform by inflammatory ILC2s in blood was increased in patients with asthma and correlated with more severe airway disease. CD45RO is a candidate biomarker for human inflammatory ILC2s that correlates with acquisition of steroid resistance.

Abstract

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.

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