microRNA Regulation of T Cell Senescence

项目概要/摘要 产生保护性疫苗反应，由T滤泡辅助细胞的成功产生控制 和长寿的记忆T细胞，随着年龄的增长越来越受损。由于microRNA是一种主要的调节因子， T细胞蛋白质组，我们假设与年龄相关的microRNA表达的变化有助于 T细胞老化的缺陷。已知微小RNA伴随着减少许多基因的表达。 靶分子，通常属于特定的功能模块。虽然对每一个人的影响 分子通常很小，信号传导和转录因子网络上的协同活动可以具有 重大影响。已知在T细胞分化过程中动态调节的microRNA包括 miR-181 a和miR-21。虽然miR-181 a的表达随着T细胞分化而下降，但miR-21显示了T细胞分化的抑制作用。 相反的模式在效应细胞中比在幼稚的CD 4 T细胞中更高。对于这两种miRNAs，来自 老年个体反映了较高的分化状态，miR 181 a减少，miR 21增加 表情miR-181 a被认为是T细胞受体信号阈值的变阻器，事实上， 由于miR-181 a的缺失和相关的双重miR-181 a的过度表达，细胞对刺激的反应性降低。 特异性磷酸酶6。在初步研究中，我们已经表明miR-21选择性地对抗T滤泡辅助细胞， 细胞分化目前的建议旨在确定这些microRNA控制的途径， 最终目标是靶向这些microRNA或它们调节的途径， 老年人接种疫苗后的记忆力。在目标1中，我们建议研究miR-181 a和miR-181 b的变化如何影响miR-181 a和miR-181 b的表达。 miR-21的表达与年龄的选择对T细胞特征性转录特征的发展 滤泡辅助细胞和T记忆细胞。具体来说，我们将研究这些microRNA如何影响 转录因子网络，包括FOXO、AP 1、BLIMP、BCL 6和TCF 1，它们对T细胞滤泡 辅助细胞和T记忆细胞分化。在目标2中，我们研究了减少miR-181 a的后果， 表达对组蛋白基因转录的影响，并确定减少组蛋白对细胞增殖的影响。 效应和记忆T细胞的核小体组织及其增殖和存活的能力。目标3将 检查pri-miR-21和/或pri-miR-181 a的转录是否可以靶向改善T细胞应答。 基于对这些pri-miRNAs转录调控的初步研究，WNT信号的激活 和抑制AP 1活性成为恢复miR-181 a1和减少miR-21的候选干预措施 表情

PROJECT SUMMARY / ABSTRACT Generation of protective vaccine responses, governed by the successful generation of T follicular helper cells and long-lived memory T cells, is increasingly impaired with age. Since microRNAs are a major regulator of the T cell proteome, we hypothesized that age-associated changes in the expression of microRNAs contribute to the defects that are seen with T cell aging. MicroRNAs are known to concomitantly reduce expression of many target molecules, frequently belonging to specific functional modules. While the effect on each of these molecules is generally small, the concerted activity on signaling and transcription factor networks can have major effects. MicroRNAs that are known to be are dynamically regulated during T cell differentiation include miR-181a and miR-21. While miR-181a expression declines with T cell differentiation, miR-21 shows the opposite pattern being higher in effector than in naïve CD4 T cells. For both miRNAs, naïve CD4 T cells from older individuals reflect a state of higher differentiation with decrease in miR181a and increase in miR21 expression. miR-181a is known as a rheostat of T cell receptor signaling thresholds, and indeed older naïve T cells are less responsive to stimulation due to the loss of miR-181a and the associated overexpression of dual specific phosphatase 6. In preliminary studies, we have shown that miR-21 selects against T follicular helper cell differentiation. The current proposal aims at identifying the pathways controlled by these microRNAs with the ultimate goal to either target these microRNAs or the pathways that they regulate to improve immune memory in older individuals after vaccination. In Aim 1, we propose to examine how the shift in miR-181a and miR-21 expression with age selects against the development of transcriptional signatures characteristic of T follicular helper cells and T memory cells. Specifically, we will examine how these microRNAs influence transcription factor networks including FOXO, AP1, BLIMP, BCL6 and TCF1 that are important for T follicular helper and T memory cell differentiation. In Aim 2, we examine consequences of reduced miR-181a expression on the transcription of histone genes and determine the consequences of reduced histones on the nucleosome organization of effector and memory T cells and their ability to proliferate and survive. Aim 3 will examine whether transcription of pri-miR-21 and/or pri-miR-181a can be targeted to improve T cell responses. Based on preliminary studies on transcriptional regulation of these pri-miRNAs, activation of WNT signaling and inhibition of AP1 activity emerge as candidate interventions to restore miR-181a1 and reduce miR-21 expression.