Ultraviolet B radiation is a potent immunosuppressive agent that inhibits cell-mediated immune responses. This biologic property contributes in a major way to the growth and development of UV-induced skin cancers. Toll-like receptors, one component of innate immune system are intricately associated with a number of dermatologic conditions. Recent experiments from my laboratory suggest that innate immunity, especially toll like receptor 4 (TLR4), may play an important role in photoimmunological processes. The hypothesis that I will test in this proposal is that UV-induced regulatory T-cells (Treg) act to inhibit the development and/or function of IFN-D producing T-cells (TC1) but not IL-17 producing T-cells (TC17). Since TLR4 deficiency directs the cell-mediated immune response towards IL-17 producing T-cells, the inability of UVinduced Treg cells to inhibit Tc17 cells results in fewer UV-induced tumors in TLR4 deficient mice. To address these issues, three specific aims are proposed. First, experiments will be conducted to assess whether regulatory T-cells develop in TLR4 knockout mice after UVB radiation exposure, and, if so, their phenotype and cytokine profile will be characterized. Then, studies will be performed to determine why regulatory T-cells either do not develop or are non-functional in TLR4 deficient mice. Finally, the implications of resistance of TLR4 deficient mice to UVB-induced immunosuppression for photocarcinogenesis will be assessed. The ultimate goal of these studies is to identify genetic loci that are involved in UV-induced immune suppression and to exploit that knowledge to develop immunopreventive and immunotherapeutic approaches for photoimmunosuppression.
Ultraviolet radiation suppresses immunological function and, in so doing, contributes to skin cancer development. Recent studies from my laboratory have suggested that mice with a mutation in the TLR4 gene are resistant to UV-induced immune suppression. This proposal will investigate the mechanistic basis for this resistance and determine whether it has an impact on UV-induced skin cancers.
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