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Retinoic Acid Receptor-Related Orphan Receptor α expressing T regulatory cells restrain allergic skin inflammation

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. Retinoic Acid Receptor-Related Orphan Receptor α expressing T regulatory cells restrain allergic skin inflammation. Science Immunology 3 (21) , eaao6923. 10.1126/sciimmunol.aao6923

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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: Published Online
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: 28 May 2020 11:30
URI: http://orca.cf.ac.uk/id/eprint/109770

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