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

Hiroaki Shime; Mizuyu Odanaka; Masaki Imai; Daisuke Sugiyama; Shoryu Takayama; Akimichi Morita; Sayuri Yamazaki

doi:10.1016/j.jid.2024.11.008

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

J Invest Dermatol. 2024 Dec 24:S0022-202X(24)03025-2. doi: 10.1016/j.jid.2024.11.008. Online ahead of print.

Authors

Hiroaki Shime¹, Mizuyu Odanaka², Masaki Imai³, Daisuke Sugiyama², Shoryu Takayama², Akimichi Morita⁴, Sayuri Yamazaki⁵

Affiliations

¹ Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Electronic address: shime@med.nagoya-cu.ac.jp.
² Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
³ Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Medical Technology and Sciences, Faculty of Health Sciences, Kyoto Tachibana University, Kyoto, Japan.
⁴ Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
⁵ Department of Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Electronic address: yamazas@med.nagoya-cu.ac.jp.

PMID: 39725158
DOI: 10.1016/j.jid.2024.11.008

Abstract

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.

Keywords: CD81; CTLA-4; Proenkephalin; Tregs; UVB.