Ultraviolet B (UVB) radiation is a potent immunosuppressive agent that inhibits cell-mediated immune responses. The mechanisms by which UVB radiation influences cell-mediated immune responses have been the subject of extensive investigation. However, there is little information on the role of innate immunity in this process. Toll-like receptors (TLRs), one component of innate immunity, are intricately associated with a number of dermatologic conditions. Our recent experiments suggest that certain components of innate immunity, especially TLR4, may play an important role in photoimmunosuppression. Using gene knockout mice, we have found that TLR4 causes UVB- induced suppression of allergic contact hypersensitivity. We have also found that CD8+ T-cells that secrete IFN-3 are effector cells of contact hypersensitivity in wild type C57BL/6 mice, whereas CD8+ T-cells that secrete IL-17 are the primary effector cells for contact hypersensitivity in TLR4 gene knockout mice. UV-induced regulatory T-cells act to inhibit the development and/or function of IFN-3 producing T-cells but not IL-17 producing T-cells. Since TLR4 deficiency directs the cell-mediated immune response towards IL-17 producing T-cells, the inability of UV-induced regulatory T-cells to inhibit IL-17 producing cells results in prevention of immunosuppression in TLR4 gene knockout mice. In this study, we will assess whether regulatory T-cells develop in TLR4 gene knockout mice after UVB radiation exposure, and, if so, characterize their phenotype and cytokine profile. We will also determine why regulatory T-cells either do not develop or are non-functional in TLR4 gene knockout mice. This study will provide useful data to evaluate the role of TLR4 in UVB induced immunosuppression. The ultimate goal of this project is to identify specific molecules that can be targeted for prevention and/or treatment.
Ultraviolet B (UVB) radiation is well known to cause skin cancers which develop when the capability of our immune system is suppressed thus facilitating growth of these tumors. In this proposal, I will perform extensive studies in mice to evaluate the mechanisms through which Toll like receptor-4 (TLR4), a key component of innate immunity, mediates immunosuppression that occurs following UVB radiation. This may allow us to identify genetic loci that are involved in UVB-induced immune suppression and to develop immunopreventive and immunotherapeutic approaches for photoimmunosuppression.
| Ahmad, Israr; Guroji, Purushotham; DeBrot, Amanda H et al. (2017) Loss of INK4a/Arf gene enhances ultraviolet radiation-induced cutaneous tumor development. Exp Dermatol 26:1018-1025 |
| Ahmad, Israr; Simanyi, Eva; Guroji, Purushotham et al. (2014) Toll-like receptor-4 deficiency enhances repair of UVR-induced cutaneous DNA damage by nucleotide excision repair mechanism. J Invest Dermatol 134:1710-1717 |
| Lewis, Wesley; Simanyi, Eva; Li, Hui et al. (2011) Regulation of ultraviolet radiation induced cutaneous photoimmunosuppression by toll-like receptor-4. Arch Biochem Biophys 508:171-7 |
