Choroidal Gamma Delta T Cells as Novel Regulators of RPE Degeneration

脉络膜 Gamma Delta T 细胞作为 RPE 变性的新型调节剂

• 批准号: 10133081
• 负责人: JIYANG CAI
• 金额: $ 40.79万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133081
• 关键词: Adoptive Transfer; Age related macular degeneration; Animals; Antigens; Aryl Hydrocarbon Receptor; Blood-Retinal Barrier; Cell Therapy; Cell physiology; Cell surface; Cells; Cellular Immunity; Cholesterol; Choroid; Chronic; Clonal Expansion; Coculture Techniques; Degenerative Disorder; Dependence; Development; Diabetic Retinopathy; Diet; Dietary Intervention; Dietary Phytochemical; Dietary Supplementation; Disease; Disease susceptibility; Epidermis; Epithelial; Epithelial Cells; Event; Fatty acid glycerol esters; Flow Cytometry; Gene Expression; Growth Factor; Homeostasis; Immune; Immune response; Immunologic Surveillance; Indoles; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-1; Interleukin-10; Interleukin-17; Interleukin-4; Intervention; Intestinal Mucosa; Knock-out; Knockout Mice; Ligation; Literature; Lymphocyte; Lymphoid Cell; Measures; Microglia; Modeling; Monitor; Mus; Natural Immunity; Nuclear Orphan Receptor; Organ; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Phytochemical; Population; Production; Property; Publishing; RNA analysis; Recovery; Reporting; Resolution; Retina; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Role; Severities; Site; Sterility; Structure of retinal pigment epithelium; Supplementation; Synthetic Diet; System; T cell therapy; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Testing; Tissues; Toxic effect; Tretinoin; Vascular blood supply; age related; base; conditional knockout; cytokine; epithelial injury; immune activation; immune function; immunoregulation; innovation; interleukin-23; intraepithelial; macrophage; neurosensory; novel; pathogen; prevent; protective effect; recruit; repaired; response; retinal damage; sodium iodate; transcriptome; transcriptome sequencing; γδ T cells

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.

项目摘要 视网膜色素上皮（RPE）的变性是在各种视网膜病变中常见的病理事件。 老年性黄斑变性和色素性视网膜炎等疾病。视网膜色素上皮是视网膜外膜的一部分， 将脉络膜血液供应与神经感觉视网膜分开的血视网膜屏障。RPE损伤激活 视网膜和脉络膜隔室免疫细胞。这些反应可以促进修复和恢复， 上皮，或引起进一步的组织损伤和免疫病理学。控制炎症的机制， 外视网膜和脉络膜中的免疫功能在很大程度上还不清楚。阐明了 RPE和免疫细胞对于更好地了解疾病的发展和进展至关重要。联系我们 细胞是一组非常规的、先天性的淋巴细胞，对细胞介导的免疫具有强效作用， 上皮屏障我们发现，脉络膜巨噬细胞T细胞在应对RPE时具有新的保护功能， 通过其与RPE的功能性相互作用而损伤。CD 34 + T细胞缺陷小鼠显示对 碘酸钠诱导的RPE损伤和视网膜毒性;过继性转移的CD 4 + T细胞逆转了这一点 致敏免疫调节细胞因子，如白细胞介素4、10和17，由脉络膜炎性细胞因子T产生。 细胞通过芳烃受体（AhR）依赖机制。因此，收养转移AhR- 在碘酸钠模型中，缺乏的CD 34 + T细胞对RPE损伤没有保护作用。根据来自 根据我们已发表的和初步的研究，在目前的建议中，我们假设脉络膜血管紧张素转换酶 淋巴细胞通过AhR依赖性机制调节外视网膜中的组织稳态。三 具体目标将用于检验假设。目的1是表征脉络膜炎性T细胞功能， 慢性视网膜色素上皮变性。目的2是确定AhR在激活 脉络膜炎性T细胞及其调节性细胞因子的产生。目的3是确定是否调制 食物中植物化学物质引起的AhR活性影响脉络膜炎性T细胞对RPE的保护作用 退化从拟议的研究结果将确定是否增强脉络膜炎性T细胞功能， 是治疗涉及RPE变性的视网膜疾病的潜在的新的干预策略。

项目成果

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The Protective Role of IL-36/IL-36R Signal in Con A-Induced Acute Hepatitis.

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IL-33 in COVID-19: friend or foe?

• DOI: 10.1038/s41423-021-00685-w
• 发表时间: 2021-06
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• 通讯作者: Sun J

MTOR-initiated metabolic switch and degeneration in the retinal pigment epithelium.

• DOI: 10.1096/fj.202000612r
• 发表时间: 2020-09
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Go YM;Zhang J;Fernandes J;Litwin C;Chen R;Wensel TG;Jones DP;Cai J;Chen Y
• 通讯作者: Chen Y