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| Status |
Public on Jan 28, 2021 |
| Title |
Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
9 samples of 1 celltype, 3 conditions with 3 replicates
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| Contributor(s) |
van der Ploeg EK, Golebski K, van Nimwegen M, Fergusson JR, Heesters BA, Martinez-Gonzalez I, Kradolfer CM, van Tol S, de Bruijn MJ, de Boer GM, Tramper-Stranders GA, Braunstahl G, van IJcken W, Nagtegaal AP, van Drunen CM, Fokkens WJ, Huylebroeck D, Spits H, Hendriks RW, Stadhouders R, Bal SM |
| Citation(s) |
33514640 |
| Submission date |
May 19, 2020 |
| Last update date |
Apr 28, 2021 |
| Contact name |
Balthasar Adrianus Heesters |
| Organization name |
Utrecht University
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| Department |
Pharmaceutical Sciences
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| Lab |
Heesters
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| Street address |
Universiteitsweg 99
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| City |
Utrecht |
| State/province |
Utrecht |
| ZIP/Postal code |
3584 CG |
| Country |
Netherlands |
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| Platforms (1) |
| GPL23126 |
[Clariom_D_Human] Affymetrix Human Clariom D Assay [transcript (gene) version] |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA633849 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE150846_RAW.tar |
200.3 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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