Influence of Age on CD4 T Memory Cells

年龄对 CD4 T 记忆细胞的影响

• 批准号: 10633224
• 负责人: JORG J GORONZY
• 金额: $ 42.29万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633224
• 关键词: ATAC-seq; Accounting; Adjuvant; Adult; Age; Animal Model; Antigens; Binding; Biogenesis; CD4 Positive T Lymphocytes; Cell Compartmentation; Cell Separation; Cell physiology; Cells; Chromatin; Clinical; Complement; Data; Defect; Development; Early Endosome; Educational process of instructing; Effector Cell; Elderly; Endosomes; Enzymes; Epigenetic Process; FOXO1A gene; Failure; Functional disorder; Generations; Genes; Genetic Transcription; Goals; Heterogeneity; Human; Immune; Immune system; Immunity; Immunologic Memory; Impairment; In Vitro; Individual; Infection; Interferon Activation; Interferons; Longevity; Maps; Memory; Mitochondria; Multivesicular Body; Nature; Oxidative Phosphorylation; Pathway interactions; Population; Process; Recycling; Regulation; Shapes; Signal Transduction; System; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Transcriptional Regulation; Vaccination; Vaccines; Viral; Virus; Virus Diseases; WNT Signaling Pathway; Zoster Vaccine; antigen-specific T cells; beta catenin; effector T cell; epigenetic regulation; exhaust; experience; gene regulatory network; glycogen synthase kinase 3 beta; human old age (65+); improved; in vivo; late endosome; latent infection; memory CD4 T lymphocyte; memory process; prevent; response; senescence; success; synergism; tool; trait; transcription factor; transcriptome; vaccine response; vaccine strategy; vaccine trial; young adult

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.

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 通过感染和疫苗接种诱导。记忆T细胞的产生由转录因子控制 与调节效应T细胞的网络不同。 T细胞存储器的耐用性是可变的， 暗示记忆T细胞在转录和表观遗传调节水平上是异质的， 确定寿命。随着年龄的增长，保护性免疫力越来越受到损害，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 转录因子表达的转移，不利于记忆细胞的产生，特别是缺乏FOXO1 和TCF7表达。初步证据表明，旧激活t中的FOXO1表达降低 细胞会损害溶酶体蛋白水解活性，并诱导内体晚期室的扩张和 能够对GSK-3β进行顺序的多细胞体，从而稳定β-catenin。并行，年龄较大 活化的T细胞无法更新与早期结合的干扰素响应基因SAMD9和SAMD9L 内体并促进其融合到成熟的内体。 GSK-3β活性的抑制作用可调节 许多细胞功能，包括Wnt信号传导和TCF7活性以及线粒体生物发生，所有这些 记忆细胞产生和寿命的重要过程。基于这些数据，我们提出了较旧的t 与年轻个体相比 对GSK-3β螯合的影响。我们将在体外AIM 1和 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 检查年龄相关的转录因子FOXO1和干扰素表达的差异 响应基因SAMD9/SAMD9L形状内体隔室以及这些差异如何影响 控制记忆细胞开发的信号传导和转录因子途径。在AIM 2中，我们将检查 直接离体是否在存储单元隔室内的异质性，考虑到差异 保护，与转录因子网络相关。我们将在抗原特异性内存上执行ATAC-SEQ T细胞推断转录因子结合并确定年龄的影响，煽动病毒的性质和 疫苗状况。