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 ofdermatologic conditions. Recent experiments from my laboratory suggest that innate immunity, especiallytoll like receptor 4 (TLR4), may play an important role in photoimmunological processes. The hypothesisthat I will test in this proposal is that UV-induced regulatory T-cells (Treg) act to inhibit the developmentand/or function of IFN-D producing T-cells (TC1) but not IL-17 producing T-cells (TC17). Since TLR4deficiency directs the cell-mediated immune response towards IL-17 producing T-cells, the inability of UVinducedTreg cells to inhibit Tc17 cells results in fewer UV-induced tumors in TLR4 deficient mice. Toaddress these issues, three specific aims are proposed. First, experiments will be conducted to assesswhether regulatory T-cells develop in TLR4 knockout mice after UVB radiation exposure, and, if so, theirphenotype and cytokine profile will be characterized. Then, studies will be performed to determine whyregulatory T-cells either do not develop or are non-functional in TLR4 deficient mice. Finally, the implicationsof resistance of TLR4 deficient mice to UVB-induced immunosuppression for photocarcinogenesis will beassessed. The ultimate goal of these studies is to identify genetic loci that are involved in UV-inducedimmune suppression and to exploit that knowledge to develop immunopreventive and immunotherapeuticapproaches for photoimmunosuppression.
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