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RORα-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. ORCID: https://orcid.org/0000-0002-2243-4964, 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

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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: 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: 25 Oct 2022 22:09
URI: https://orca.cardiff.ac.uk/id/eprint/109770

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