Malhotra, Nidhi, Leyva-Castillo, Juan Manuel, Jadhav, Unmesh, Barreiro, Olga, Kam, Christy, O'Neill, Nicholas K., Meylan, Francoise, Chambon, Pierre, von Andrian, Ulrich H., Siegel, Richard M., Wang, Eddie C., Shivdasani, Ramesh and Geha, Raif S. 2018. RORα-expressing T regulatory cells restrain allergic skin inflammation. Science Immunology 3 (21) , eaao6923. 10.1126/sciimmunol.aao6923 |
|
PDF
- Accepted Post-Print Version
Download (13MB) | Preview |
Abstract
Atopic dermatitis is an allergic inflammatory skin disease characterized by the production of the type 2 cytokines in the skin by type 2 innate lymphoid cells (ILC2s) and T helper 2 (TH2) cells, and tissue eosinophilia. Using two distinct mouse models of atopic dermatitis, we show that expression of retinoid-related orphan receptor α (RORα) in skin-resident T regulatory cells (Tregs) is important for restraining allergic skin inflammation. In both models, targeted deletion of RORα in mouse Tregs led to exaggerated eosinophilia driven by interleukin-5 (IL-5) production by ILC2s and TH2 cells. Expression of RORα in skin-resident Tregs suppressed IL-4 expression and enhanced expression of death receptor 3 (DR3), which is the receptor for tumor necrosis factor (TNF) family cytokine, TNF ligand–related molecule 1 (TL1A), which promotes Treg functions. DR3 is expressed on both ILC2s and skin-resident Tregs. Upon deletion of RORα in skin-resident Tregs, we found that Tregs were no longer able to sequester TL1A, resulting in enhanced ILC2 activation. We also documented higher expression of RORα in skin-resident Tregs than in peripheral blood circulating Tregs in humans, suggesting that RORα and the TL1A-DR3 circuit could be therapeutically targeted in atopic dermatitis.
Item Type: | Article |
---|---|
Date Type: | Publication |
Status: | Published |
Schools: | Medicine |
Publisher: | American Association for the Advancement of Science |
ISSN: | 2470-9468 |
Funders: | MRC |
Date of First Compliant Deposit: | 9 March 2018 |
Date of Acceptance: | 17 January 2018 |
Last Modified: | 18 Jan 2021 21:23 |
URI: | http://orca-mwe.cf.ac.uk/id/eprint/109770 |
Citation Data
Cited 23 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
![]() |
Edit Item |