microRNA Regulation of T Cell Senescence

描述(由申请人提供)：老化的免疫系统启动适应性免疫反应的能力降低，损害了疫苗接种的效果，并增加了感染的发病率。对外源性或内源性威胁的适应性免疫反应依赖于多样化的T细胞库和抗原特异性T细胞的快速激活和扩增 填充和获取效应器功能。在研究年龄对CD4T细胞功能的影响时，我们发现miR181a的下降是T细胞老化的特征标志。到目前为止，我们的研究主要集中在双特异性磷酸酶(DUSP)6，它被miR181a抑制，因此随着年龄的增长而双向增加。DUSP6校准T细胞受体激活阈值，在该阈值上，刺激被转化为产生信号。DUSP6的增加导致了老年T细胞对反应的敏感性降低。MiRNAs通过抑制一组基因的翻译发挥作用，这些基因通常属于相关的途径。目前的建议是基于这样的假设，即miR181a和共同调节的miR181b的下降对于理解T细胞衰老具有广泛的重要性，并且其后果超出了DUSP6活性的增加。除了DUSP6，我们还将重点介绍SIRT1、BCL-2和TCL1。DUSP6和SIRT1的共同之处在于它们控制着T细胞激活的负反馈回路。SIRT1、BCL-2和TCL1是T细胞生存通路的重要组成部分。因此，miR181a/b的下降导致T细胞表型，以牺牲激活和效应器功能为代价，有利于细胞的长寿和静止。在目标1中，我们将研究控制miR181a/b表达的表观遗传、转录和转录后机制。这些研究的目的是了解是什么导致miR181a/b随年龄下降，并找出上调表达的方法。目的检测AGE对T细胞亚群中SIRT1、BCL-2和TCL1表达的影响，并确定与年龄相关的蛋白表达变化是否由miR181a/b的表达程度引起，以及miR181a/b的过度表达是否可以逆转。在目标3中，我们将研究miR181a/b缺失的功能后果，并确定它们是否可归因于DUSP6、SIRT1、TCL1或bCL-2的过度表达。

DESCRIPTION (provided by applicant): The reduced ability of the aging immune system to mount adaptive immune responses compromises the efficacy of vaccinations and increases the morbidity from infections. Adaptive immune responses to exogenous or endogenous threats rely on a diverse T cell repertoire and the rapid activation and expansion of an antigen-specific T cell population and acquisition of effector functions. In studying the effect of age on CD4 T cell function, we have identified a decline in miR181a as a characteristic hallmark of T cell aging. Our studies so far have focused on the dual-specific phosphatase (DUSP) 6 which is repressed by miR181a and therefore reciprocally increases with age. DUSP6 calibrates the T cell receptor activation threshold at which stimulation is translated into a productive signal. Increased DUSP6 contributes to the lowered sensitivity of elderly T cells to respond. miRNAs function by repressing the translation of sets of genes, frequently belonging to related pathways. The current proposal is based on the hypothesis that the decline in miR181a and the co-regulated miR181b is of broad importance to understand T cell aging and has consequences that go beyond increased DUSP6 activity. In addition to DUSP6, we will focus on SIRT1, BCL-2, and TCL1. What DUSP6 and SIRT1 have in common is that they control negative feedback loops in T cell activation. SIRT1, BCL-2 and TCL1 are critical components of T cell survival pathways. The decline in miR181a/b therefore results in a T cell phenotype that favors cellular longevity and quiescence at the expense of activation and effector function. In Aim 1, we will examine the epigenetic, transcriptional and post-transcriptional mechanisms that control miR181a/b expression. The objectives of these studies are to understand what drives the decline in miR181a/b with age and to identify means to upregulate expression. Aim 2 will examine the influence of age on the expression of SIRT1, BCL-2, and TCL1 in T cell subsets and determine whether age-related changes in protein expression are caused by the degree of miR181a/b expression and can be reversed by miR181a/b overexpression. In Aim 3, we will examine the functional consequences of miR181a/b loss, and we will determine whether they can be attributed to the overexpression of DUSP6, SIRT1, TCL1 or BCL-2.