Peripherally induced RORγt ⁺ skin-resident regulatory T cells mediate the efficacy of allergen-specific immunotherapy

Skin-resident regulatory T cells (T_reg cells) cells play a critical role in subcutaneous allergen-specific immunotherapy (SIT) for atopic dermatitis (AD). However, a detailed description of the phenotype and origin of skin-resident T_reg cells during SIT is lacking. Therefore, we investigated the role and origin of specific T_reg lineages in SIT with human AD samples and with a mouse model of AD. In the blood of patients with AD who responded to SIT, T_reg cells showed a notable increase in retinoic acid-related orphan receptor γt (RORγt) expression. Moreover, RORγt-expressing T_reg cells expanded in the skin of patients with AD upon SIT. In a mouse model of AD, the absence of RORγt expression in skin T_reg cells led to reduced therapeutic efficacy with SIT. In addition, SIT-induced RORγt⁺ T_reg cells originated from peripheral tissue rather than from the thymus. Using two-photon microscopy and a parabiosis mouse model, we observed the migration and accumulation of skin-resident RORγt⁺ T_reg cells in response to the SIT-induced immune response. These findings indicate that SIT induces peripheral RORγt⁺ T_reg cell expansion, which contributes to the therapeutic efficacy of SIT.