Aging and IL-7 mediated CD8+ T cell survival

衰老和 IL-7 介导的 CD8 T 细胞存活

• 批准号: 10207438
• 负责人: Insoo Kang
• 金额: $ 36.85万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207438
• 关键词: Activities of Daily Living; Address; Affect; Age; Aging; Allogenic; Biological; Biological Assay; CD8-Positive T-Lymphocytes; CX3C Chemokines; Cell Culture Techniques; Cell Survival; Cells; Chemotaxis; Collaborations; Cytomegalovirus; Cytomegalovirus Infections; DNA; DNA Methylation; DNA Methylation Regulation; Development; Elderly; Endothelial Cells; Fractalkine; Gene Expression; Gene Expression Regulation; Genes; Goals; Human; IL7 gene; IL7R gene; Immune; Immune response; Immune system; Immunity; Implant; Infection; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukin 7 Receptor; Interleukin-15; Interleukin-6; Length; Light; Maintenance; Malignant Neoplasms; Mediating; Memory; Mus; Pathway interactions; Peripheral Blood Mononuclear Cell; Population; Process; Production; Publishing; Recording of previous events; Regulation; Regulator Genes; Role; Secondary to; Serology; Signal Pathway; Site; T cell response; T-Cell Development; T-Lymphocyte; TNF gene; Testing; Up-Regulation; age effect; base; chemokine; chemokine receptor; cytokine; cytotoxic; fractalkine receptor; genome-wide; healthy aging; humanized mouse; interest; perforin; peripheral blood; promoter; response; telomere; tissue injury; trait; transcription factor; young adult

Project Summary/Abstract: Alterations in the immune system occur with aging, likely contributing to the development of infections and malignancies. Although the latter finding suggests an age-associated decline of the immune system, aging could be regarded as a condition with dysregulated inflammation (inflammaging). In T cell immunity, probably, the most prominent change with aging is the expansion of memory CD8+ T cells in peripheral blood although its exact mechanism(s) and significance are yet to be determined. My lab investigated whether the expansion of human memory CD8+ T cells with aging was secondary to increased expression of IL-7 receptor alpha chain (IL-7Rα) which dictates the response to the pro-survival cytokine IL-7. We found two cell populations which expressed low and high levels of IL-7Rα (IL-7Rαlow and high) in effector memory (EM) CD8+ T cells in peripheral blood. Of interest, older adults (OA, age ≥ 65) had expansion of IL- 7Rαlow EM CD8+ T cells (up to 70% of total CD8+ T cells), which are largely cytotoxic and inflammatory cytokine producing cells, compared to young adults (YA, age ≤ 40). Such cell expansion is associated with cytomegalovirus infection, which persists for lifetime, as well as with enhanced production of and proliferative response to IL-15 that promotes the maintenance and effector function of memory CD8+ T cells. However, the significance of the expansion of IL-7Rαlow EM CD8+ T cells in OA remains largely unknown, especially in the context of inflammation. To address this critical question, we performed a genome-wide DNA methylation analysis in IL-7Rαlow and high EM CD8+ T cells since DNA methylation modulates gene expression. IL-7Rαlow EM CD8+ T cells have hypomethylation of DNA in a group of chemotaxis-associated genes, including CX3CR1 (receptor for fractalkine), with enhanced expression. Plus, we noticed increased CX3CR1 expression by IL- 7Rαlow EM CD8+ T cells in OA compared to YA as well as the effect of aging on DNA methylation of the CX3CR1 promoter in the same cells. Thus, we hypothesize that aging “qualitatively” enhances the pro- inflammatory traits of human IL-7Rαlow EM CD8+ T cells by affecting gene regulatory mechanisms, including DNA methylation and IL-15-mediated responses in addition to expanding them and that soluble factors produced from such cells promote inflammation by activating other cells. This hypothesis will be tested with: Aim 1. Investigate whether aging promotes IL-7Rαlow EM CD8+ T cell-mediated inflammatory response in humans by altering inflammatory gene regulation via DNA methylation and transcription factors; Aim 2. Elucidate age-associated alterations in IL-15-mediated inflammatory response in human IL-7Rαlow EM CD8+ T cells; and Aim 3. Investigate the significance of age-associated alterations of IL-7Rαlow EM CD8+ T cells in promoting inflammatory responses using ex vivo bioassay and humanized mice. Our results will shed light on the biological significance of expanded memory CD8+ T cells with aging, especially in the aspect of inflammation, as well as on the possible role of gene regulations in promoting this process.

项目摘要/摘要：随着年龄的增长，免疫系统会发生变化，这可能会导致 感染和恶性肿瘤的发展。尽管后一项发现表明，与年龄相关的 免疫系统的老化可以被认为是一种炎症(炎症)失调的状态。在……里面 T细胞免疫，随着年龄的增长，最显著的变化可能是记忆中CD8+T细胞的扩张 外周血的确切作用机制(S)和意义尚不清楚。我的实验室 研究了人类记忆CD8+T细胞随年龄增长的扩增是否继发于增龄 IL-7受体α链(IL-7Rα)的表达，它决定了对促生存细胞因子IL-7的反应。 我们在效应器中发现了低水平和高水平表达IL-7Rα(IL-7Rα低水平和高水平)的两个细胞群 外周血中的记忆(EM)CD8+T细胞。有趣的是，老年人(OA，65岁，≥)有IL-2的扩张。 7Rα低EMCD8+T细胞(高达总CD8+T细胞的70%)，主要是细胞毒和炎性细胞因子 产生细胞，与年轻人(YA，年龄≤40岁)相比。这种单元格扩展与 巨细胞病毒感染，这种感染持续终生，并伴随着增加的产量和增殖性 对IL-15的反应，促进记忆CD8+T细胞的维持和效应功能。然而， IL-7Rα低EMCD8+T细胞在骨性关节炎中的意义尚不清楚，尤其是在骨性关节炎 炎症的背景。为了解决这个关键问题，我们进行了全基因组DNA甲基化 IL-7Rα低、高EMCD8+T细胞甲基化调控基因表达的分析IL-7Rα低电平 EM CD8+T细胞存在包括CX3CR1在内的一组趋化相关基因的DNA低甲基化 (Fractalkine受体)，表达增强。此外，我们注意到IL-1增加了CX3CR1的表达。 7Rα低EMCD8+T细胞在骨性关节炎和慢性再生障碍性关节炎中的比较及增龄对其甲基化的影响 CX3CR1启动子在同一细胞中。因此，我们假设衰老在质量上增强了人的健康。 影响基因调控机制的人IL-7Rα低EMCD8+T细胞炎症特性 DNA甲基化和IL-15介导的反应以及它们和可溶性因子 由这种细胞产生的物质通过激活其他细胞来促进炎症。这一假设将通过以下几个方面进行验证： 目的1.探讨增龄是否促进IL-7Rα低EMCD8+T细胞介导的炎症反应 人类通过DNA甲基化和转录因子改变炎症基因调控；目标2。 人IL-7Rα低EMCD8+T细胞IL-15介导的炎症反应的增龄变化 目的3.探讨IL-7Rα低EMCD8+T细胞增龄变化的意义 使用体外生物测定和人源化小鼠促进炎症反应。我们的结果将为我们提供 扩增记忆CD8+T细胞在增龄过程中的生物学意义 炎症，以及基因调控在促进这一过程中可能发挥的作用。