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老化而发生，可能有助于 感染和恶性肿瘤的发展。尽管后一个发现表明与年龄相关的下降 免疫系统衰老可以视为注射失调（炎症）的疾病。 T细胞免疫，可能是随着衰老的最突出变化是记忆CD8+ T细胞的扩展 外周血尽管其确切的机制和显着性尚待确定。我的实验室 研究了人类记忆的扩展CD8+ T细胞的衰老是否是继发的 IL-7受体α链（IL-7Rα）的表达，该链决定了对生存性细胞因子IL-7的反应。 我们发现两个细胞群在效应子中表达低水平和高水平的IL-7Rα（IL-7Rαlow和High） 记忆（EM）CD8+ T细胞在外周血中。有趣的是，老年人（OA，年龄≥65岁）的IL- 7rαlowem CD8+ T细胞（最多占总CD8+ T细胞的70％），这些细胞主要是细胞毒性和炎性细胞因子 与年轻人相比，产生细胞（Ya，年龄≤40）。这种细胞扩展与 巨细胞病毒感染持续存在，并随着增殖和增殖而增强 对IL-15的响应促进了内存CD8+ T细胞的维护和效应函数。但是， OA中IL-7RαlowEM CD8+ T细胞扩展的重要性仍然很大未知，尤其是在 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甲基化调制基因表达，在IL-7Rαlow和高EM CD8+ T细胞中进行了分析。 IL-7Rαlow EM CD8+ T细胞在一组趋化性相关基因中的DNA低甲基化，包括CX3CR1 （分子的受体），具有增强的表达。另外，我们注意到IL-的CX3CR1表达增加了 与YA相比，OA中的7RαlowEM CD8+ T细胞以及衰老对DNA甲基化的影响 同一细胞中的CX3CR1启动子。这就是我们假设“定性”衰老增强了衰老 人类IL-7RαlowEM CD8+ T细胞的炎症性状通过影响基因调节机制，包括 DNA甲基化和IL-15介导的反应除了扩大它们以及固体因素 由这种细胞产生的通过激活其他细胞促进炎症。该假设将通过： AIM 1。研究衰老是否促进IL-7RαlowEM CD8+ T细胞介导的炎症反应 通过通过DNA甲基化和转录因子来改变炎症基因调节来改变人；目标2。 IL-15介导的人IL-7RαlowEM CD8+ T的IL-15介导的炎症反应的阐明年龄相关的改变 细胞；和目标3。研究IL-7Rαlowem CD8+ T细胞与年龄相关改变的重要性 使用离体生物测定和人源化小鼠促进炎症反应。我们的结果将阐明 随着衰老的衰老，扩展记忆CD8+ T细胞的生物学性，尤其是在 炎症以及基因调节在促进这一过程中的可能作用。