microRNA Regulation of T Cell Senescence

项目摘要/摘要 由T滤泡辅助细胞的成功产生所支配的保护性疫苗反应的产生 和长寿的记忆T细胞，随着年龄的增长而日益受损。由于microRNAs是该基因的主要调节者 T细胞蛋白质组，我们假设与年龄相关的microRNAs表达的变化有助于 T细胞老化时出现的缺陷。已知的是，microRNAs伴随着减少许多 靶分子，通常属于特定的功能模块。而对其中每一个人的影响 分子一般很小，信号和转录因子网络上的协同活动可以 主要效果。已知在T细胞分化过程中动态调节的microRNAs包括 MIR-181a和MIR-21。虽然miR-181a的表达随着T细胞的分化而下降，但miR-21显示 相反的模式在效应者中高于幼稚的CD4T细胞。对于这两个miRNAs，来自 年龄较大的个体反映出更高的分化状态，miR181a减少，miR21增加 表情。MIR-181a被认为是T细胞受体信号阈值的变阻器，实际上是较老的幼稚T细胞 由于miR-181a的丢失和相关的DUAL过表达，细胞对刺激的反应较差 在初步研究中，我们已经证明miR-21对T滤泡辅助分子具有选择性 细胞分化。目前的提案旨在通过以下方式确定这些microRNAs控制的途径 最终的目标要么是针对这些microRNAs，要么是针对它们调节的提高免疫力的途径 老年人接种疫苗后的记忆。在目标1中，我们建议研究miR-181a和miR-181a的转变 MIR-21的表达与年龄的关系不利于T细胞的转录特征 滤泡辅助细胞和T记忆细胞。具体地说，我们将研究这些microRNA如何影响 转录因子网络包括FOXO、AP1、BLIMP、BCL6和TCF1在T卵泡中起重要作用 辅助者和T记忆细胞分化。在目标2中，我们检查了miR-181a减少的后果 在组蛋白基因转录上的表达，并确定组蛋白减少对 效应T细胞和记忆T细胞的核小体组织及其增殖和存活的能力。目标3将 研究pri-miR-21和/或pri-miR-181a的转录是否可以靶向改善T细胞反应。 基于对这些pri-miRNAs转录调控的初步研究，WNT信号的激活 抑制AP1活性成为恢复miR-181a1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.