CD8 T cell fate decision instructed by IL-2

IL-2指导CD8 T细胞命运决定

• 批准号: 10740087
• 负责人: Takeshi Egawa
• 金额: $ 30万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-12 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10740087
• 关键词: ATAC-seq; Acute; Antigens; Binding; Binding Sites; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cell Differentiation process; Cell physiology; Cells; ChIP-seq; Chromatin; Chronic; Clonal Expansion; Complex; Cytokine Receptors; DNA Methylation; Data; Down-Regulation; Epigenetic Process; Frequencies; Genes; Genetic; Goals; Grant; IRF4 gene; Immune response; Immunotherapy; Inflammatory; Interleukin-12; Interleukin-15; Interleukin-2; Malignant Neoplasms; Mediating; Memory; Metabolic; Molecular; Mus; Mutagenesis; Population; Proliferating; Regulator Genes; Repression; Rest; Role; Shapes; Signal Induction; Signal Pathway; Signal Transduction; Stat5 protein; Stimulus; T cell differentiation; T cell response; T-Cell Activation; TCF Transcription Factor; TCR Activation; Testing; Transcriptional Silencer Elements; Vaccination; Virus Diseases; Virus Replication; Visit; cytokine; cytotoxic CD8 T cells; effector T cell; gene regulatory network; imprint; improved; insight; morphogens; overexpression; pathogen; permissiveness; progenitor; programmed cell death protein 1; programs; promoter; recruit; response; transcription factor; tumor; tumor growth

Abstract In response to viral infection or vaccination, antigen(Ag)-specific CD8 T cells that are present at low frequencies undergo rapid clonal expansion. While the majority of activated CD8 T cells become terminally differentiated effector T (TEFF) cells following expansion and die after Ag clearance, a small fraction of them persists as memory cells (TMEM) that contribute to long-term protection. However, it remains incompletely understood how cell-extrinsic stimuli through TCR and cytokine receptors establish the gene regulatory networks that determine the fates of activated CD8 T cells. The overall goal of this grant is to dissect the molecular and cellular mechanisms by which TCR and IL-2R signaling cooperatively regulates CD8 T cell differentiation through the control of the critical transcription factor TCF-1 encoded by Tcf7. We will test the hypothesize that cooperative action between signals induced by antigen and IL-2, but not IL-15, specifically during priming induces expression of a set of transcription factors and epigenetic changes at a transcriptional silencer element in the Tcf7 locus. The establishment of stable Tcf7 repression requires the stimulation- responsive enhancement of IL-2R signaling, which establishes steady the TEFF- or TMEM-specific gene regulatory circuitry that can be stably maintained after the inducing cell extrinsic stimuli decays as immune responses resolve or become equilibrated. These studies will provide insights into the long standing question of the molecular mechanisms of CD8 T cell differentiation and potential application to programming improved immunotherapies.

摘要 在对病毒感染或疫苗接种的应答中，以低水平存在的抗原（Ag）特异性CD 8 T细胞被激活。 频率经历快速克隆扩增。虽然大多数活化的CD 8 T细胞最终成为 在扩增后分化的效应T（TEFF）细胞，并在Ag清除后死亡，其中一小部分 作为记忆细胞（TMEM）持续存在，有助于长期保护。然而，它仍然是不完全的， 了解细胞外部刺激如何通过TCR和细胞因子受体建立基因调控， 这些网络决定了活化的CD 8 T细胞的命运。这项赠款的总体目标是剖析 TCR和IL-2 R信号协同调节CD 8 T细胞的分子和细胞机制 通过Tcf 7编码的关键转录因子TCF-1的控制，细胞分化受到抑制。我们将测试 假设抗原诱导信号与IL-2而非IL-15之间的协同作用， 在引发过程中诱导一组转录因子的表达和转录水平上的表观遗传变化， Tcf 7基因座中的沉默元件。建立稳定的Tcf 7抑制需要刺激- IL-2 R信号传导的响应性增强，其建立稳定的TEFF或TMEM特异性基因 在诱导细胞的外源性刺激随着免疫应答的衰减而衰减后， 反应解决或变得平衡。这些研究将为长期存在的问题提供见解， CD 8 T细胞分化的分子机制和编程的潜在应用得到了改善 免疫疗法