Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Abstract

Exposure to UVB radiation before antigen delivery at an unirradiated site inhibits functional immunological responses. Mice treated dorsally with suberythemal lowdose UVB and immunized with ova in abdominal skin generated ova-specific CD8 T cells with a significantly decreased activation, expansion, and cytotoxic activity compared with unirradiated mice. UVB also impaired the delayed-type hypersensitivity (DTH) reaction to ova. Transfer of CD4 ؉ CD25 ؉ cells from UVB-exposed mice did not suppress the ova-specific CD8 T-cell response or DTH reaction in unexposed mice, confirming that systemic low-dose UVB does not induce long-lived functional regulatory CD4 ؉ CD25 ؉ T cells. Repairing cyclobutane pyrimidine dimer-type DNA damage and blocking aryl hydrocarbon receptor signaling also did not reverse the immunosuppressive effect of UVB on ova-specific CD8 T cells and DTH, suggesting that cyclobutane pyrimidine dimers and the aryl hydrocarbon receptor are not required in systemic low-dose UVBinduced immunosuppression. The known UVB chromophore, cis-urocanic acid, and reactive oxygen species triggered the inhibition of DTH caused by UVB, but they were not involved in the modulation of CD8 T cells. These findings indicate that systemic low-dose UVB impedes the primary response of antigen-specific CD8 T cells by a novel mechanism that is independent of pathways known to be involved in systemic suppression of DTH. UVB radiation (290 to 320 nm) in natural sunlight is a potent immunosuppressant. UVB can inhibit the immune system from generating optimal responses to tumors, contact haptens, and various microbial antigens (Ags; viral, fungal, and parasitic) that can lead to exacerbated disease. Alternatively, immunosuppressive UVB can also be beneficial to control autoimmune diseases, such as psoriasis 1 and experimental autoimmune encephalomyelitis. 2 The epidermis of skin absorbs UVB through chromophores, including nuclear DNA, cytoplasmic tryptophan, and extracellular trans-urocanic acid (UCA). The molecular processes that follow trigger a cascade of events that cumulates in the phenomenon of UVB-induced immunosuppression. Some of the hallmarks of this immunosuppression include UVB-induced genetic mutations in skin cells, circulation of cis-UCA from the isomerization of trans-UCA, production of reactive oxygen species (ROS), and generation of regulatory T and B cells that can transfer suppression into UVB-naïve mice. 3 Because UVB has both detrimental and beneficial effects on the immune system, it is critical to understand the mechanisms regulated by UVB so that effective prophylactic and palliative therapies can be designed for skin diseases, such as skin cancer, and immune-mediated diseases in internal organs, such as multiple sclerosis.A previous study 4 showed that UVB can inhibit CD8 and CD4 T-cell responses to haptens. In a model of contact hypersensitivity (CHS), we demonstrated that a low dose of UVB (approximately 5 minutes of summer sunlight in Sydney, Australia, at midday) is sufficient to inhibit the activati...

Treatment of Non-Segmental Vitiligo with Narrowband UVB Phototherapy (311 Nm): Clinical Efficacy and Mechanisms of Action

“…Probably, it can be explained by the fact that the dose of radiation received by patients in that study was twice lower than in our work. At the same time, there are publications about ability of UVB radiation to inhibit CD4 and CD8 cells and skin inflammation which are consistent with results of our studies regarding reduction of these cell populations in the skin of patients with vitiligo under the influence of phototherapy [30,31].…”

Photoimmunology and Multiple Sclerosis

“…2). UVB affects CD8 + cytotoxic T lymphocyte (CTL) responses (Rana et al 2011), as well as suppressing CD4 + T helper cell (Th) type 1 (Th1) (Brown et al 1995), Th2 (McGlade et al 2007) and Th17 (Singh et al 2010) responses. UVB suppression of the T cell response is likely to be important in protection from MS because CTLs (Mars et al 2011) as well as Th1 and Th17 responses are strong drivers of CNS-targeted autoimmunity (Zamvil et al 1986;Lock et al 2002;Langrish et al 2005;Tzartos et al 2008;Yang et al 2008;Sweeney et al 2011;Inoue et al 2012).…”

“…While it is now appreciated that UVB suppresses immunity in internal organs as well as the skin Rana et al 2011), the trigger must have a cutaneous origin as UVB does not penetrate deep enough to reach internal organs. Two early molecular events following UVB exposure is the release of plateletactivating factor (PAF) from keratinocytes Alappatt et al 2000) and the isomerisation of epidermal trans-urocanic acid (UCA) to cis-UCA (Anglin et al 1961;Pascher 1962).…”

The suppressive effects of ultraviolet radiation on immunity in the skin and internal organs: Implications for autoimmunity

“…In the spleen, low doses of UVB (0.5 MED; 150 mJ/cm 2 ) can inhibit the primary activation and expansion of antigen-specific CD8 T cells against protein antigens. Functionally, these cells also have impaired in vivo cytotoxic activity [35]. Using hen egg ovalbumin (OVA) as a model tumour antigen, Toda et al has shown that very high dose UVB (calculated to be about 8 MED; 2300 mJ/cm 2 ) promotes the growth of OVA-transgenic tumour cells which are rejected in unirradiated immunised mice.…”

“…These routes of antigen application can drain into separate lymphoid organs not directly draining the site of irradiation, and yet UVB still influences immunity within these tissues [34][35][36][37]. In the spleen, low doses of UVB (0.5 MED; 150 mJ/cm 2 ) can inhibit the primary activation and expansion of antigen-specific CD8 T cells against protein antigens.…”