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.