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

  • Sci Immunol. 2021 Jan 29;6(55):eabd3489. doi: 10.1126/sciimmunol.abd3489.
Esmee K van der Ploeg  1  2 ,  Korneliusz Golebski  3  4 ,  Menno van Nimwegen  1 ,  Joannah R Fergusson  3 ,  Balthasar A Heesters  3 ,  Itziar Martinez-Gonzalez  3 ,  Chantal M A Kradolfer  3 ,  Sophie van Tol  3 ,  Brendon P Scicluna  5  6 ,  Marjolein J W de Bruijn  1 ,  Geertje M de Boer  1  7 ,  Gerdien A Tramper-Stranders  8  9 ,  Gert-Jan Braunstahl  1  7 ,  Wilfred F J van IJcken  2  10 ,  A Paul Nagtegaal  11 ,  Cornelis M van Drunen  12 ,  Wytske J Fokkens  12 ,  Danny Huylebroeck  2 ,  Hergen Spits  13 ,  Rudi W Hendriks  1 ,  Ralph Stadhouders  14  2 ,  Suzanne M Bal  1  3
Affiliations
  • 1. Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands.
  • 2. Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands.
  • 3. Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
  • 4. Department of Respiratory Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
  • 5. Center of Experimental and Molecular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
  • 6. Department of Clinical Epidemiology and Biostatistics, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
  • 7. Department of Respiratory Medicine, Franciscus Gasthuis and Vlietland, Rotterdam, Netherlands.
  • 8. Department of Pediatric Medicine, Franciscus Gasthuis and Vlietland, Rotterdam, Netherlands.
  • 9. Department of Neonatology, Sophia Children's Hospital, Erasmus MC, Rotterdam, Netherlands.
  • 10. Center for Biomics, Erasmus MC, Rotterdam, Netherlands.
  • 11. Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, Rotterdam, Netherlands.
  • 12. Department of Otorhinolaryngology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands.
  • 13. Department of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands. [email protected] [email protected].
  • 14. Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands. [email protected] [email protected].
PMID: 33514640 DOI: 10.1126/sciimmunol.abd3489
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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