Molecular Mechanisms Of Memory T Cell Response and Aging

记忆 T 细胞反应和衰老的分子机制

• 批准号: 7592053
• 负责人: Nan-ping Weng
• 金额: $ 75.19万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592053
• 关键词: Acetylation; Aging; Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Chromatin; Gene Expression; Genes; Genetic Transcription; Goals; Histone H3; Histones; Human; In Vitro; Interphase Cell; Lysine; Mediating; Memory; Methods; Modeling; Modification; Molecular; Molecular Profiling; Numbers; Pathway interactions; Pattern; Phenotype; Play; Property; Rest; Role; Staging; T memory cell; T-Lymphocyte; Tissue-Specific Gene Expression; base; cohort; day; in vivo; interest; response

The majority of highly activated CD4+ T cell effectors die after antigen clearance, but a small number revert to a resting state, becoming memory cells with unique functional attributes. It is currently unclear when after antigen clearance effectors return to rest and acquire important memory properties. We follow well-defined cohorts of CD4+ T cells through the effector-to-memory transition by analyzing phenotype, important functional properties, and gene expression profiles. We find that the transition from effector to memory is rapid in that effectors rested for only 3 days closely resemble canonical memory cells rested for 60 days or longer in the absence of antigen. This is true for both Th1 and Th2 lineages, and occurs whether CD4+ T cell effectors rest in vivo or in vitro, suggesting a default pathway. We find that the effector memory transition at the level of gene expression occurs in two stages: a rapid loss of expression of a myriad of effector-associated genes, and a more gradual gain of expression of a cohort of genes uniquely associated with memory cells rested for extended periods. To understand the molecular basis for the rapid and robust memory T cell responses, we examined gene expression and chromatin modification by histone H3 lysine 9 (H3K9) acetylation in resting and activated human nave and memory CD8+ T cells. We found that, although overall gene expression patterns were similar, a number of genes are differentially expressed in either memory or nave cells in their resting and activated states. To further elucidate the basis for differential gene expression, we assessed the role of histone H3K9 acetylation in differential gene expression. Strikingly, higher H3K9 acetylation levels were detected in resting memory cells, prior to their activation, for those genes that were differentially expressed following activation, indicating that hyperacetylation of histone H3K9 may play a role the selective and rapid gene expression of memory CD8+ T cells. Consistent with this model, we showed that inducing high levels of H3K9 acetylation resulted in an increased expression in nave cells of those genes that are normally expressed differentially in memory cells. Together, these findings suggest that differential gene expression mediated at least in part by histone H3K9 hyperacetylation may be responsible for the rapid and robust memory CD8+ T cell response.

大多数高度激活的CD4+ T细胞效应子在抗原清除率后死亡，但少量数量恢复为静止状态，成为具有独特功能属性的存储单元。目前尚不清楚抗原清除效应器何时恢复休息并获得重要的内存属性。我们通过分析表型，重要的功能特性和基因表达谱，遵循效应子到内存过渡的CD4+ T细胞的明确定义。我们发现，在没有抗原的情况下，效应子从效应子到记忆的过渡迅速持续了3天。对于TH1和TH2谱系都是如此，并且发生CD4+ T细胞效应子在体内或体外都存在，这表明默认途径。我们发现，基因表达水平的效应子记忆转变在两个阶段发生：迅速丧失了与效应子相关的基因的表达迅速丧失，并且更逐渐地获得了与记忆细胞唯一相关的基因的表达。为了理解快速和稳健记忆T细胞反应的分子基础，我们在静止和激活的人中介于的静息和活化的人中心和记忆CD8+ T细胞中检查了组蛋白H3赖氨酸9（H3K9）乙酰化的基因表达和染色质修饰。我们发现，尽管总体基因表达模式相似，但许多基因在其静止和活化态中的记忆或中殿细胞中差异表达。为了进一步阐明差异基因表达的基础，我们评估了组蛋白H3K9乙酰化在差异基因表达中的作用。引人注目的是，在激活之前，在静息记忆细胞中检测到较高的H3K9乙酰化水平，对于那些激活后差异表达的基因，表明组蛋白H3K9的高乙酰化可能在选择性和快速的基因表达中的记忆CD8+ T细胞中发挥作用。与该模型一致，我们表明诱导高水平的H3K9乙酰化导致通常在记忆细胞中差异表达的基因的中殿细胞表达增加。总之，这些发现表明，至少部分由组蛋白H3K9高乙酰化介导的差异基因表达可能导致了快速，健壮的记忆CD8+ T细胞反应。