Choroidal Gamma Delta T Cells as Novel Regulators of RPE Degeneration

项目总结 摘要视网膜色素上皮(RPE)变性是各种视网膜常见的病理事件。 老年性黄斑变性和视网膜色素变性等疾病。RPE是外部 血视网膜屏障，将脉络膜血液供应与神经感觉视网膜隔开。RPE损伤被激活 视网膜和脉络膜室免疫细胞。这些反应既可以促进修复和恢复 或造成进一步的组织损伤和免疫病理。控制炎症的机制和 外视网膜和脉络膜的免疫功能在很大程度上还不清楚。澄清两国之间的相互作用 RPE和免疫细胞对于更好地了解疾病的发展和进展是至关重要的。T 细胞是一组非常规的、与生俱来的淋巴细胞，在细胞免疫中具有强大的作用。 上皮性屏障。我们发现脉络膜T细胞对视网膜色素上皮具有新的保护功能 通过它们与RPE的功能相互作用而受到伤害。T细胞缺陷小鼠对 碘酸钠诱导的视网膜色素上皮损伤和视网膜毒性；过继转移T细胞可逆转这一点 敏化。免疫调节细胞因子，如白介素4、10和17，由脉络膜T产生 细胞通过芳香烃受体(AhR)依赖的机制。因此，通过转让AhR- 在碘酸钠模型中，缺乏T细胞对视网膜色素上皮损伤没有保护作用。基于以下研究结果： 我们已发表的和初步的研究，在目前的建议中，我们假设脉络膜T 淋巴细胞通过AhR依赖的机制调节视网膜外的组织动态平衡。三 具体的目标将被用来检验这一假设。目的1是表征脉络膜T细胞的功能。 慢性RPE变性条件。目的2是确定AhR在激活AHR中的机制作用。 脉络膜T细胞及其调节性细胞因子的产生。目标3是确定调制是否 饲料中植物化学物质的活性影响脉络膜T细胞对RPE的保护作用 退化。拟议研究的结果将确定是否增强脉络膜T细胞功能 是一种潜在的治疗涉及RPE变性的视网膜疾病的新的介入策略。

PROJECT SUMMARY Degeneration of the retinal pigment epithelium (RPE) is a pathological event commonly seen in various retinal diseases such as age-related macular degeneration and retinitis pigmentosa. The RPE is part of the outer blood retinal barrier that separates choroidal blood supply from the neurosensory retina. RPE injury activates retinal and choroidal compartment immune cells. The responses can either promote repair and recovery of the epithelium, or cause further tissue damage and immune pathology. Mechanisms controlling inflammation and immune functions in the outer retina and choroid are largely unclear. Clarifying the interactions between the RPE and immune cells is crucial for a better understanding of disease development and progression.  T cells are a group of unconventional, innate-like lymphocytes with potent effects on cell-mediated immunity near the epithelial barrier. We found that choroidal  T cells have novel protective functions in response to RPE injury through their functional interactions with the RPE.  T cell-deficient mice show increased sensitivity to sodium iodate-induced RPE damage and retinal toxicity; adoptive transfer of  T cells reverses this sensitization. Immune regulatory cytokines, such as interleukins 4, 10 and 17, are produced by choroidal  T cells via aryl hydrocarbon receptor (AhR)-dependent mechanisms. Accordingly, adoptive transfer of AhR- deficient  T cells is not protective against RPE injury in the sodium iodate model. Based on the findings from our published and preliminary studies, in the current proposal we hypothesize that choroidal  T lymphocytes regulate tissue homeostasis in the outer retina via AhR-dependent mechanisms. Three specific aims will be used to test the hypothesis. Aim 1 is to characterize choroidal  T cell function during chronic RPE degeneration conditions. Aim 2 is to determine the mechanistic role of AhR in activation of choroidal  T cells and their production of regulatory cytokines. Aim 3 is to determine whether modulating AhR activity by dietary phytochemicals will influence the protective effects of choroidal  T cells against RPE degeneration. The results from the proposed studies will define whether enhancing choroidal  T cell function is potentially a novel interventional strategy for treating retinal diseases that involve RPE degeneration.