RORα-expressing T regulatory cells restrain allergic skin inflammation

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 (T_H2) 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 (T_regs) is important for restraining allergic skin inflammation. In both models, targeted deletion of RORα in mouse T_regs led to exaggerated eosinophilia driven by interleukin-5 (IL-5) production by ILC2s and T_H2 cells. Expression of RORα in skin-resident T_regs 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 T_reg functions. DR3 is expressed on both ILC2s and skin-resident T_regs Upon deletion of RORα in skin-resident T_regs, we found that T_regs were no longer able to sequester TL1A, resulting in enhanced ILC2 activation. We also documented higher expression of RORα in skin-resident T_regs than in peripheral blood circulating T_regs in humans, suggesting that RORα and the TL1A-DR3 circuit could be therapeutically targeted in atopic dermatitis.