Accumulating evidence shows that immunological tolerance induced by Ag administration together with UVB irradiation is dependent on Foxp3+ CD4+ regulatory T (Treg) cells. However, the mechanisms by which UVB controls Treg cells in the skin are currently unclear. In this study, we have shown that exposure to UVB induced expansion of Treg cells up to 50–60% of the CD4+ T cells in the irradiated skin. The Treg cell expansion in the skin lasted for 2 wk after exposure, which contributed to homeostasis of Treg cells in the periphery later. UVB-expanded Treg cells formed clusters with dendritic cells and proliferated in situ. Furthermore, the expanded Treg cells appeared to derive from neuropilin 1+ thymus-derived Treg (tTreg) cells in the periphery because UVB-expanded Treg cells possessed Treg cell–specific CpG hypomethylation pattern, as seen in tTreg cells. These results collectively indicate that homeostasis of tTreg cells is controlled by UVB exposure in the skin. UVB therapy may be useful for not only inflammatory skin disorders, but also autoimmunity, transplantation, and allergy.

Skin dendritic cells (DCs) are divided into several subsets with distinctive functions. This study shows a previously unappreciated role of dermal CD11b-type Langerin DCs in maintaining immunological self-tolerance after UVB exposure. After UVB exposure, dermal CD11b-type Langerin DCs upregulated surface CD86 expression, induced proliferation of Foxp3 regulatory T (Treg) cells without exogenous Ags, and upregulated a set of genes associated with immunological tolerance. This Treg-expansion activity was significantly hampered by CD80/CD86 blockade in vivo. These results indicate that CD11b-type Langerin DCs from the UVB-exposed skin are specialized to expand Treg cells in the skin, which suppress autoimmunity.

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Premature skin aging occurs as a result of repeated exposure to ultraviolet (UV) radiations and/or other oxidative stress inducers (pollution, cigarette). Nicotinamide (NAM) is a precursor of NAD+ well-known for its benefits on skin. However, little is known about how NAM impacts photoaged skin, or more widely, skin submitted to oxidative stress. We first showed that oxidative stress induced accelerated differentiation of human primary keratinocytes (HPKs) in 2D cultures. Indeed, UVB exposure increased differentiation in a dose-dependent manner, characterized by an upregulation of epidermal differentiation markers (keratins 1, 10, 13, filaggrin and involucrin). A similar effect on differentiation was observed after H 2 O 2 treatment, and was correlated to a massive senescence. Strikingly, NAM (1.5mM) prevented both the accelerated differentiation and the senescence phenotypes in 2D cultures. In 3D organotypic models, UVB induced a loose basket weave-like appearance of the stratum corneum and a thickening of the granular layers accompanied by an increase in filaggrin and loricrin staining, thus confirming our 2D data showing an enhanced differentiation process after UV exposure. By contrast, increasing doses of NAM from 1.5 to 15mM led to a gradual thinning of the epidermis and loss of differentiation markers. However, the basal cell layer remained present, with a percentage of Ki67-positive (i.e. proliferating) cells comparable to the control. In conclusion, we found that NAM slows down keratinocyte differentiation but maintains proliferation following H 2 O 2 or UV exposure. Collectively, our data show a positive effect of NAM in fighting oxidative stress through a modulation of the proliferation/ differentiation balance of HPK stem cells, which could potentially be related to its anti-aging properties.