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：免疫系统随着衰老而发生变化，可能导致 感染和恶性肿瘤的发展。尽管后一个发现表明年龄相关的下降 对于免疫系统来说，衰老可以被视为炎症失调（炎症）的病症。在 T 细胞免疫，随着衰老最显着的变化可能是记忆 CD8+ T 细胞的扩张。 外周血，但其确切机制和意义尚未确定。我的实验室 研究了人类记忆 CD8+ T 细胞随衰老的扩展是否继发于增加 IL-7 受体 α 链 (IL-7Rα) 的表达决定了对促生存细胞因子 IL-7 的反应。 我们发现效应细胞中表达低水平和高水平 IL-7Rα（IL-7Rα 低和高）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，年龄 ≥ 65 岁）的 IL- 7Rαlow EM CD8+ T 细胞（占 CD8+ T 细胞总数的 70%），主要是细胞毒性和炎症细胞因子 与年轻人（YA，年龄 ≤ 40 岁）相比，产生细胞。这种细胞扩张与 巨细胞病毒感染，终生持续，并且巨细胞病毒的产生和增殖增强 对 IL-15 的反应可促进记忆 CD8+ T 细胞的维持和效应功能。然而， IL-7Rαlow EM CD8+ T 细胞在 OA 中扩增的意义仍然很大程度上未知，特别是在 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 由于 DNA 甲基化调节基因表达，因此对 IL-7Rα 低和高 EM CD8+ T 细胞进行分析。 IL-7Rα低 EM CD8+ T 细胞的一组趋化相关基因（包括 CX3CR1）的 DNA 低甲基化 （fractalkine 的受体），表达增强。另外，我们注意到 IL- 增加了 CX3CR1 的表达 OA 中的 7Rαlow EM CD8+ T 细胞与 YA 相比以及衰老对 OA 中 DNA 甲基化的影响 CX3CR1 启动子位于同一细胞中。因此，我们假设衰老“定性地”增强了亲和力。 通过影响基因调控机制来改变人 IL-7Rαlow EM CD8+ T 细胞的炎症特征，包括 DNA 甲基化和 IL-15 介导的反应除了扩大它们和可溶性因子 这些细胞产生的物质通过激活其他细胞来促进炎症。该假设将通过以下方法进行检验： 目标 1. 研究衰老是否会促进 IL-7Rαlow EM CD8+ T 细胞介导的炎症反应 通过 DNA 甲基化和转录因子改变炎症基因调控；目标2。 阐明人 IL-7Rαlow EM CD8+ T 中 IL-15 介导的炎症反应与年龄相关的变化 细胞；目标 3. 研究 IL-7Rαlow EM CD8+ T 细胞年龄相关变化的意义 使用离体生物测定和人源化小鼠促进炎症反应。我们的结果将揭示 记忆扩展 CD8+ T 细胞随衰老的生物学意义，特别是在以下方面 炎症，以及基因调控在促进这一过程中可能发挥的作用。