UVB Irradiation Expands Skin-Resident CD81⁺Foxp3⁺ Regulatory T Cells with a Highly Activated Phenotype

Exposure to UVB induces the expansion of regulatory T cells (Tregs) expressing proenkephalin and amphiregulin with a healing function in the skin. It is unclear how this UVB exposure affects the functionally distinct subsets of skin Tregs. In this study, we have demonstrated that skin-resident CD81⁺Tregs expressing both proenkephalin gene Penk and amphiregulin gene Areg expanded after UVB irradiation. CD81⁺Tregs in UVB-irradiated skin as well as in normal skin exhibited a highly activated state. Foxp3, BLIMP-1, and IRF4, which transcriptionally enhance Treg function-related molecules, were also highly expressed in UVB-expanded CD81⁺Tregs. Notably, UVB-expanded skin CD81⁺Tregs constitutively expressed on their cell surface CTLA-4, a critical molecule for Treg-mediated immune suppression. CD81⁺Tregs exhibited suppressive activity against CD4⁺T-cell proliferation. Stimulation of CD81 enhanced the proliferation of Foxp3⁺Tregs under CD3 and CD28 stimulation in vitro, indicating that CD81 acts as a costimulatory molecule. Blocking CD81 partially resulted in reduced Treg expansion in the skin of UVB-irradiated mice. These results suggest that CD81 is a representative marker of highly activated Tregs in normal and UVB-irradiated skin and may represent a functional molecule that controls Treg expansion in the skin in response to UVB irradiation.