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

ABSTRACT: Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and tissue homeostatis, but have also been implicated in major human type 2 immunopathologies. However, our understanding of the mechanisms that control human ILC2 activity and phenotypic heterogeneity under inflammatory conditions remains limited. We integrated transcriptome profiling, flowcytometry characterization and functional assays to characterize human ILC2s from non-inflamed and inflamed microenvironments. We show that the transition from a resting to an activated inflammatory state in ILC2s is accompanied by a CD45RA-to-CD45RO isoform switch. CD45RA phosphatase activity suppresses ILC2 activation in resting cells, while exposure to activating cytokines induces IRF4/BATF transcription factors to promote a switch to the enzymatically restrained CD45RO isoform. Importantly, CD45RO+ ILC2 levels are increased in nasal polyps but also in the circulation of patients with chronic rhinosinusitis and asthma, which correlates with disease severity and resistance to steroid therapy. CD45RA-to-CD45RO conversion in ILC2s is sensitive to suppression by glucocorticosteroids, a mainstay therapy for patients with type-2 inflammatory disease. However, once converted, CD45RO+ ILC2s are resistant to steroids, likely via unique intrinsic metabolic reprogramming. In summary, we identify an inflammatory ILC2 subset in humans that is marked by CD45RO and is linked to severe type-2 inflammatory disease and steroid resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150846 | GEO | 2021/01/28

REPOSITORIES: GEO

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