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：免疫系统的改变随着年龄的增长而发生，可能导致 感染和恶性肿瘤的发展。尽管后一项发现表明， 在免疫系统中，衰老可以被认为是具有失调的炎症（炎症）的状况。在 随着年龄的增长，T细胞免疫可能最突出的变化是记忆性CD 8 + T细胞的扩增， 外周血，尽管其确切的机制和意义还有待确定。我的实验室 研究人类记忆性CD 8 + T细胞随着衰老的扩增是否继发于增加 IL-7受体α链（IL-7 R α）的表达，决定了对促存活细胞因子IL-7的应答。 我们发现两个细胞群表达低和高水平的IL-7 R α（IL-7 R α低和高）， 外周血中的记忆（EM）CD 8 + T细胞。值得注意的是，老年人（OA，年龄≥ 65岁）的IL-10水平增加， 7 R α降低EM CD 8 + T细胞（高达总CD 8 + T细胞的70%），其主要是细胞毒性和炎性细胞因子 与年轻人（YA，年龄≤ 40岁）相比，这种细胞扩张与 巨细胞病毒感染，持续终身，以及与增强的生产和增殖 免疫调节剂是对IL-15的应答，其促进记忆性CD 8 + T细胞的维持和效应子功能。但 在OA中IL-7 R α低EM CD 8 + T细胞扩增的意义在很大程度上仍然未知，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， 分析IL-7 R α低和高EM CD 8 + T细胞，因为DNA甲基化调节基因表达。IL-7 R α低 EM CD 8 + T细胞在一组趋化相关基因中具有DNA低甲基化，包括CX 3CR 1 （fractalkine的受体），具有增强的表达。另外，我们注意到IL-10可增加CX 3CR 1的表达。 与YA相比，OA中的7 R α低EM CD 8 + T细胞以及衰老对OA细胞DNA甲基化的影响。 CX 3CR 1启动子。因此，我们假设衰老“定性”地增强了亲- 人IL-7 R α通过影响基因调控机制降低EM CD 8 + T细胞的炎症特性，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之外 由这些细胞产生的蛋白质通过激活其他细胞来促进炎症。该假设将通过以下方式进行检验： 目标1.研究衰老是否促进IL-7 R α低EM CD 8 + 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;目的2. 阐明人IL-7 R α低EM CD 8 + T细胞中IL-15介导的炎症反应的年龄相关变化 细胞;和目标3.研究IL-7 R α低EM CD 8 + T细胞的年龄相关性改变的意义 使用离体生物测定和人源化小鼠促进炎症反应。我们的研究结果将揭示 扩增的记忆性CD 8 + T细胞在衰老中的生物学意义，特别是在 炎症，以及基因调控在促进这一过程中的可能作用。