Dietary grape seed proanthocyanidins inactivate regulatory T cells by promoting NER-dependent DNA repair in dendritic cells in UVB-exposed skin

// Mudit Vaid 2, * , Ram Prasad 1, 2, * , Tripti Singh 2 and Santosh K. Katiyar 1, 2 1 Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA 2 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA * These authors contributed equally to this work Correspondence to: Santosh K. Katiyar, email: skatiyar@uab.edu Keywords: grape proanthocyanidins, ultraviolet radiation, photocarcinogenesis, contact hypersensitivity, regulatory T cells Received: March 16, 2017      Accepted: April 29, 2017      Published: May 15, 2017 ABSTRACT Ultraviolet B (UVB) radiation induces regulatory T cells (Treg cells) and depletion of these Treg cells alleviates immunosuppression and inhibits photocarcinogenesis in mice. Here, we determined the effects of dietary grape seed proanthocyanidins (GSPs) on the development and activity of UVB-induced Treg cells. C3H/HeN mice fed a GSPs (0.5%, w/w)-supplemented or control diet were exposed to UVB (150 mJ/cm 2 ) radiation, sensitized to 2,4-dinitrofluorobenzene (DNFB) and sacrificed 5 days later. FACS analysis indicated that dietary GSPs decrease the numbers of UVB-induced Treg cells. ELISA analysis of cultured sorted Treg cells indicated that secretion of immunosuppressive cytokines (interleukin-10, TGF-β) was significantly lower in Treg cells from GSPs-fed mice. Dietary GSPs also enhanced the ability of Treg cells from wild-type mice to stimulate production of IFNγ by T cells. These effects of dietary GSPs on Treg cell function were not found in XPA -deficient mice, which are incapable of repairing UVB-induced DNA damage. Adoptive transfer experiments revealed that naive recipients that received Treg cells from GSPs-fed UVB-irradiated wild-type donors that had been sensitized to DNFB exhibited a significantly higher contact hypersensitivity (CHS) response to DNFB than mice that received Treg cells from UVB-exposed mice fed the control diet. There was no significant difference in the CHS response between mice that received Treg cells from UVB-irradiated XPA -deficient donors fed GSPs or the control diet. Furthermore, dietary GSPs significantly inhibited UVB-induced skin tumor development in wild-type mice but not in XPA -deficient mice. These results suggest that GSPs inactivate Treg cells by promoting DNA repair in dendritic cells in UVB-exposed skin.