Ultraviolet-B irradiation expands skin-resident CD81⁺Foxp3⁺ regulatory T cells with a highly activated phenotype

Exposure to ultraviolet-B (UVB) induces the expansion of regulatory T (Treg) cells expressing proenkephalin (PENK) and amphiregulin (AREG) with a healing function in the skin. It is unclear how this UVB exposure affects the functionally distinct subsets of skin Treg cells. In this study, we have demonstrated that skin-resident CD81⁺Treg cells expressing both Penk and Areg expanded after UVB irradiation. CD81⁺Treg cells 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⁺Treg cells. Notably, UVB-expanded skin CD81⁺Treg cells constitutively expressed on their cell surface CTLA-4, a critical molecule for Treg-mediated immune suppression. CD81⁺Treg cells exhibited suppressive activity against CD4⁺T cell proliferation. Stimulation of CD81 enhanced the proliferation of Foxp3⁺Treg cells under CD3 and CD28 stimulation in vitro, indicating that CD81 acts as a co-stimulatory 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 Treg cells in normal and UVB-irradiated skin, and may represent a functional molecule that controls Treg expansion in the skin in response to UVB irradiation.