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Aging and IL-7 mediated CD8+ T cell survival

衰老和 IL-7 介导的 CD8 T 细胞存活

基本信息

批准号：
9764233
负责人：
Insoo Kang
金额：
$ 36.85万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/9764233
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 IL7R gene Immune Immune response Immune system Immunity Implant Infection Inflammaging Inflammation Inflammatory Inflammatory Response Injury Interferons Interleukin 7 Receptor Interleukin-15 Interleukin-6 Interleukin-7 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 Serologic tests Signal Pathway Site T cell response T-Cell Development T-Lymphocyte TNF gene Testing Tissues 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 trait transcription factor young adult

项目摘要

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，免疫系统会发生改变，这可能与