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

Abstract

Skin-resident regulatory T cells (Treg 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 Treg cells during SIT is lacking. Therefore, we investigated the role and origin of specific Treg 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, Treg cells showed a notable increase in retinoic acid-related orphan receptor gamma t (ROR gamma t) expression. Moreover, ROR gamma t-expressing Treg cells expanded in the skin of patients with AD upon SIT. In a mouse model of AD, the absence of ROR gamma t expression in skin Treg cells led to reduced therapeutic efficacy with SIT. In addition, SIT-induced ROR gamma t+ Treg 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 ROR gamma t+ Treg cells in response to the SIT-induced immune response. These findings indicate that SIT induces peripheral ROR gamma t+ Treg cell expansion, which contributes to the therapeutic efficacy of SIT.