1 INTRODUCTION
A commonly used therapy in dermatology, narrowband ultraviolet B (UVB)exerts immunosuppressive effects on the skin to attenuate central nervous system autoimmunity1 and prevent atherosclerosis2 by regulating systemic inflammatory responses. UVB-induced immunosuppression can be hapten-specific, based on a mouse model of hapten-induced contact hypersensitivity (CHS), where UVB suppressed skin phenotypes but skin sensitized to unrelated haptens remained unaffected.3 Results of a separate study where an injection of splenocytes from UVB-tolerized mice into naive mice also indicated skin phenotype suppression.4 Other studies have shown that UVB irradiation with alloantigen immunization can protect allografts from rejection.5,6 Even though UVB can induce peripheral tolerance to a specific antigen, the mechanism remains unclear.
Previous work has implicated the expansion of regulatory T cells (Tregs) by UVB.1,2,7,8 Various immune responses,including autoimmunity, transplant rejection, antitumor immunity, and allergy9-11, are suppressed by Tregs, of which there are two types: thymus-derived Tregs (tTregs) and peripheral Tregs (pTregs).12 Treg development in the thymus is associated with high-affinity interaction between TCR and major histocompatibility complex (MHC)-peptide, while pTreg differentiation in the periphery can be induced under sub-immunogenic conditions.13,14 Peripheral Tregs are known to play an indispensable role in the control of immunity at inflammatory tissue sites.15,16 Some studies have suggested the conversion of memory or effector T cells to Tregs in vitro and in peripheral tissues. Kim et al. showed that antigen-specific memory Th2 cells are induced to differentiate into Foxp3+ Tregs by TGF-β, all-trans retinoic acid, and rapamycin.17 Amarnath et al. found that human Th1 cells are converted to Foxp3+ Tregs under programmed death ligand-1 (PD-L1) stimulation.18 Thus, pTregs may control local inflammatory responses, such as in the skin, and show clinical significance for autoimmune diseases.
In the present study, we aimed to investigate the mechanism underlying the induction of antigen-specific Tregs by UVB, which confers peripheral tolerance to an antigen. We report the effects of UVB on human peripheral CD4+ T cells in a prospective UVB phototherapy trial using cytometry by time-of-flight (CyTOF). Mouse models of OVA-induced skin inflammation and allogeneic skin transplantation were used to validate antigen-specific Treg induction under UVB treatment. We performed adoptive transfer experiments to investigate the role of UVB-induced antigen-specific Tregs in disease modulation. Using single-cell RNA (scRNA) sequencing analysis, we sought to illustrate the detailed pathway of Treg differentiation from CD4+ T cells and understand how UVB induces antigen-specific Tregs in human peripheral tissues.