RORα-expressing T regulatory cells restrain allergic skin inflammation

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Science Immunology  02 Mar 2018:
Vol. 3, Issue 21, eaao6923
DOI: 10.1126/sciimmunol.aao6923

Curbing ILC2 enthusiasm

Atopic dermatitis is an allergic disease driven by type 2 immune responses in the skin. Using mouse models of dermatitis, Malhotra et al. have identified tumor necrosis factor (TNF) family cytokine, TNF ligand–related molecule 1 (TL1A), and its receptor death receptor 3 (DR3) as being critical in regulating cross-talk between skin-resident T regulatory cells (Tregs) and type 2 innate lymphoid cells (ILC2) that drive skin inflammation. They report that retinoid-related orphan receptor α (RORα) drives expression of DR3 in Tregs and that, upon deletion of RORα, skin-resident Tregs are unable to sequester TL1A that drives effector functions of ILC2s. The studies open up the possibility of targeting the TL1A-DR3 in the context of dermatitis and other skin allergies.


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.

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