Role of the Innate Immune System in Regulation of UVB Induced Skin Carcinogenesis

紫外线B辐射是一种有效的免疫抑制剂，可抑制细胞介导的免疫反应。 这种生物学特性在很大程度上促进了紫外线诱导的皮肤癌的生长和发展。 Toll样受体是先天性免疫系统的一个组成部分，与许多免疫系统相关。 皮肤病我的实验室最近的实验表明，先天免疫，特别是 Toll样受体4（TLR 4）可能在光免疫过程中起重要作用。的假设 我将在这个建议中测试的是，紫外线诱导的调节性T细胞（Treg）的作用是抑制发展， 和/或产生IFN-D的T细胞（TC 1）而不是产生IL-17的T细胞（TC 17）的功能。由于TLR 4 缺乏将细胞介导的免疫应答导向产生IL-17的T细胞， Treg细胞抑制Tc 17细胞导致TLR 4缺陷小鼠中较少的UV诱导的肿瘤。到 针对这些问题，提出了三个具体目标。首先，将进行实验以评估 UVB辐射暴露后TLR 4敲除小鼠中是否会产生调节性T细胞，如果是，它们的 将表征表型和细胞因子谱。然后，将进行研究，以确定为什么 调节性T细胞在TLR 4缺陷小鼠中不发育或无功能。最后， TLR 4缺陷小鼠对UVB诱导的光致癌免疫抑制的抗性将是 评估。这些研究的最终目标是确定参与紫外线诱导的遗传位点。 免疫抑制和开发免疫预防和免疫治疗知识 用于光免疫抑制的方法。

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.