Role of Telomere And Telomerase In Human Lymphocyte Function and Aging

端粒和端粒酶在人类淋巴细胞功能和衰老中的作用

• 批准号: 7592052
• 负责人: Nan ping Peter Weng
• 金额: $ 80.2万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592052
• 关键词: Age; Aging; Alzheimer' s Disease; CD28 gene; CD8B1 gene; CD94 Antigen; Caregivers; Cell Aging; Cell division; Cell physiology; Cells; Chronic stress; Condition; Employee Strikes; Expression Feature; Gender; Gene Expression; Goals; Human; Immune; In Vitro; Individual; Interleukin-10; Interleukin-15; Length; Longevity; Lymphocyte; Lymphocyte Function; Memory; Molecular; Molecular Profiling; Patients; Peripheral Blood Mononuclear Cell; Production; Regulation; Role; T memory cell; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Subsets; TNF gene; Telomerase; cell age; cell growth; cytokine; depressive symptoms; immune function; in vivo; monocyte; psychologic; receptor; response; telomere

Accumulation of CD28-CD8+ T cells that are defective in response to antigenic stimulation is a hallmark of age-associated decline in T cell function. However, the underlying mechanism of this age-associated change is not fully understood. We recently analyzed the global gene expression profiles of CD8+ T cell subsets from nave to memory (CD28+ to CD28-) cells and the growth of CD28+ and CD28- CD8+ memory T cells in response to homeostatic cytokine interleukin 15 (IL-15). At the gene expression level, one of the most striking changes is the altered expression of some co-stimulatory receptors and various NK cell receptors in CD28-CD8+ T cells. Furthermore, CD28-CD8+ T cells appear to have a normal proliferation response to IL-15 in vitro. Interestingly, IL-15 is also capable of inducing stable loss of CD28 expression in actively dividing CD28+CD8+ memory T cells. Together, these findings provide the gene expression features of CD28-CD8+ T cells that differ from their CD28+ counterparts and suggest a possible role of IL-15 in the increase of CD28-CD8+ T cells that occurs with aging. Caregivers of Alzheimers disease (AD) patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, peripheral blood mononuclear cell (PBMC) composition, in vitro activation induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p<0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF- and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 Kb, respectively, p<0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p<0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T-cell function and accelerated immune cell aging as suggested by excessive telomere loss.

响应抗原刺激有缺陷的CD28-CD8+ T细胞的积累是与年龄相关的T细胞功能下降的标志。但是，这种相关变化的基本机制尚未完全理解。我们最近分析了CD8+ T细胞子集从中殿到记忆（CD28+至CD28-）细胞的全局基因表达谱以及CD28+和CD28- CD8- CD8+记忆T细胞的生长，响应稳态细胞因子介体介体介体15（IL-15）。在基因表达水平上，最引人注目的变化之一是CD28-CD8+ T细胞中某些共刺激受体和各种NK细胞受体的表达改变。此外，CD28-CD8+ T细胞在体外似乎对IL-15具有正常的增殖反应。有趣的是，IL-15还能够在主动分裂CD28+ CD8+记忆T细胞中诱导CD28表达的稳定丧失。总之，这些发现提供了与CD28+对应物不同的CD28-CD8+ T细胞的基因表达特征，并提出IL-15在随着衰老而发生的CD28-CD8+ T细胞的增加中的可能作用。 阿尔茨海默氏病（AD）患者的护理人员忍受与免疫功能下降有关的慢性应激。为了评估护理人员的心理和免疫学变化，我们比较了抑郁症状，外周血单核细胞（PBMC）组成，体外激活诱导的增殖和细胞因子的产生以及远距离的长度和端粒酶活性82个个体（41个护理人员以及41个年龄及41个年龄和性别对照组）。我们发现，护理人员的抑郁症状明显高于对照组（p <0.001）。相应地，护理人员的T细胞增殖明显降低，但在体外刺激的响应中，免疫调节细胞因子（TNF-和IL-10）的产生较高。 We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 Kb, respectively, p<0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC.最后，我们表明，PBMC和T细胞中的基础端粒酶活性在护理人员中明显高于对照组（P <0.0001），这表明细胞试图不成功，以补偿护理人员中远程触点过多的损失。这些发现表明，慢性应激与T细胞功能的改变和加速的免疫细胞衰老有关，如端粒损失过多所暗示。