Photodermatological Effects of Toll Like Receptor-4 (TLR4)

描述(由申请人提供)：紫外线B(UVB)辐射是一种有效的免疫抑制剂，可以抑制细胞介导的免疫反应。UVB辐射影响细胞免疫反应的机制一直是广泛研究的主题。然而，关于先天免疫在这一过程中的作用的信息很少。Toll样受体(TLRs)是天然免疫的一个组成部分，与多种皮肤病密切相关。我们最近的实验表明，天然免疫的某些成分，特别是TLR4，可能在光免疫抑制中发挥重要作用。利用基因敲除小鼠，我们发现TLR4可以抑制UVB诱导的过敏性接触性超敏反应。我们还发现，在野生型C57BL/6小鼠中，分泌干扰素-3的CD8+T细胞是接触性超敏反应的效应细胞，而在TLR4基因敲除小鼠中，分泌IL-17的CD8+T细胞是接触性超敏反应的主要效应细胞。紫外线诱导的调节性T细胞可抑制产生干扰素-3的T细胞的发育和/或功能，但不能抑制产生IL-17的T细胞。由于TLR4缺乏将细胞免疫反应导向产生IL-17的T细胞，紫外线诱导的调节性T细胞不能抑制产生IL-17的细胞，从而防止了TLR4基因敲除小鼠的免疫抑制。在这项研究中，我们将评估TLR4基因敲除小鼠在UVB辐射暴露后是否发育调节性T细胞，如果是，则表征其表型和细胞因子谱。我们还将确定为什么调节性T细胞在TLR4基因敲除小鼠中要么不发育，要么不起作用。本研究为评价TLR4在UVB诱导的免疫抑制中的作用提供了有用的数据。该项目的最终目标是确定可用于预防和/或治疗的特定分子。 与公众健康相关：众所周知，紫外线B(UVB)辐射会导致皮肤癌，当我们的免疫系统能力受到抑制时，皮肤癌就会发展，从而促进这些肿瘤的生长。在这项提议中，我将在小鼠身上进行广泛的研究，以评估先天免疫的关键组成部分Toll样受体-4(TLR4)介导UVB辐射后发生的免疫抑制的机制。这可能使我们能够确定与UVB诱导的免疫抑制有关的遗传位点，并开发光免疫抑制的免疫预防和免疫治疗方法。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.