Influence of Age on CD4 T Memory Cells

项目摘要/摘要 免疫系统发展免疫记忆的能力是保护性免疫的基础 由感染和接种疫苗引起的。记忆T细胞的产生受转录因子的控制 不同于调节效应器T细胞的网络。T细胞存储器的耐久性是可变的， 这意味着记忆T细胞在转录和表观遗传调控水平上是异质性的 决定长寿。随着年龄的增长，保护性免疫能力越来越弱，这意味着 记忆细胞的产生和存活。在我们对老年人T细胞反应的体外研究中，我们发现 转录因子表达的改变，不利于记忆细胞的产生，特别是缺乏FOXO1 和Tcf7的表达。初步证据表明，老年活化T细胞中FOXO1的表达减少 细胞损害溶酶体的蛋白分解活性，并诱导晚期内小体的隔室扩张和 能够隔离葛兰素史克-3β，从而稳定β-连环蛋白的多囊体。同时，更老的 活化的T细胞不能上调早期结合的干扰素反应基因SAMD9和SAMD9L 内体并促进它们的融合成熟为晚期的内体。抑制葛兰素史克-3β活性调节 许多细胞功能，包括WNT信号和Tcf7活性以及线粒体的生物发生，都 记忆细胞产生和寿命的重要过程。基于这些数据，我们提出了较老的T 与年轻个体相比，激活后的细胞在其内体/溶酶体系统中形成不同， 对葛兰素史克-3β封存的影响。我们将在体外机制目标1中检验这一假说 Aim 2中抗原特异性记忆T细胞中转录因子网络的体内研究。在Aim 1中，我们将 研究转录因子FOXO1和干扰素表达的年龄相关性差异 反应基因SAMD9/SAMD9L形成内体隔室以及这些差异如何影响 控制记忆细胞发育的信号和转录因子途径。在目标2中，我们将研究 是否直接在体外异质性的记忆细胞隔间，占差异在 保护，与转录因子网络相关。我们将对抗原特异性记忆进行ATAC-SEQ T细胞来推断转录因子的结合并确定年龄、激发病毒的性质和 疫苗状态。

PROJECT SUMMARY / ABSTRACT The ability of the immune system to develop immunological memory is the basis for protective immunity induced by infection and vaccination. Generation of memory T cells is governed by transcription factor networks that are different from those regulating effector T cells. Durability of T cell memory is variable, implying that memory T cells are heterogeneous at the level of transcriptional and epigenetic regulation that determine longevity. Protective immunity is increasingly compromised with age, implying a defect in the generation and survival of memory cells. In our in vitro studies of T cell responses from older adults, we found a shift in transcription factor expression that disfavored memory cell generation, in particular a lack of FOXO1 and TCF7 expression. Preliminary evidence suggests that the reduced FOXO1 expression in old activated T cells impairs lysosomal proteolytic activity and induces expansion of the compartment of late endosomes and multivesicular bodies that are able to sequestrate GSK-3β and thereby stabilize β-catenin. In parallel, older activated T cells fail to upregulate the interferon response genes SAMD9 and SAMD9L that bind to early endosomes and facilitate their fusion to mature into late endosome. Inhibition of GSK-3β activity regulates many cellular functions including WNT signaling and TCF7 activity as well as mitochondrial biogenesis, all important processes for memory cell generation and longevity. Based on these data, we propose that older T cells upon activation develop differences in their endosomal/lysosomal system compared to young individuals, with implications for GSK-3β sequestration. We will examine this hypothesis in a mechanistic in vitro Aim 1 and in vivo studies of transcription factor networks in antigen-specific memory T cells in Aim 2. In Aim 1, we will examine how age-associated differences in the expression of the transcription factor FOXO1 and the interferon response genes SAMD9/SAMD9L shape endosomal compartments and how these differences influence signaling and transcription factor pathways that control memory cell development. In Aim 2, we will examine directly ex vivo whether heterogeneity within the memory cell compartment, accounting for differences in protection, correlates with transcription factor networks. We will perform ATAC-seq on antigen-specific memory T cells to infer transcription factor binding and determine the influence of age, nature of inciting virus and vaccine status.