CTCF in CD8 T cell homeostasis and anti-viral/tumor immunity

CTCF 在 CD8 T 细胞稳态和抗病毒/肿瘤免疫中的作用

• 批准号: 10584273
• 负责人: Weiqun Peng
• 金额: $ 54.23万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584273
• 关键词: 3-Dimensional; Adoptive Cell Transfers; Algorithms; Architecture; Binding; Biological Assay; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular biology; Chromatin; Communicable Diseases; Development; Elements; Engineered Gene; Follow-Up Studies; Foundations; Funding; Gene Expression Regulation; Genome; Genomics; Goals; Homeostasis; IL7 gene; Immune response; Immunocompetence; Immunotherapy; Interleukin-15; Knowledge; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Mature T-Lymphocyte; Mediating; Memory; Molecular; Molecular Analysis; Multiomic Data; Nature; Output; Pathway interactions; Pattern; Preventive vaccine; Progress Reports; Regulation; Research; Research Design; Resolution; Role; SELL gene; Supervision; Systems Biology; T cell differentiation; T-Lymphocyte; Therapeutic; Thymus Gland; Transcriptional Regulation; Tumor Antigens; Tumor Immunity; Vaccines; Viral; Viral Antigens; Viral Cancer; Virus Diseases; antiviral immunity; cell transformation; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; cytotoxic; engineered T cells; epigenetic regulation; flexibility; frontier; genome-wide; improved; in vivo; inducible gene expression; insight; novel; pathogen; rational design; response; stem; transcription factor; tumor; tumor microenvironment

CD8+ T lymphocytes are essential players in mounting protective cellular immune responses against pathogens and malignantly transformed cells. To sustain immunocompetency, the naïve CD8+ T cell pool must be maintained at a stable size. Upon activation, naïve CD8+ T cells differentiate into cytotoxic effector and memory cells that clear pathogens and provide heightened long-term protection, respectively. With the advent of demonstrated efficacy of adoptive cell therapy using naturally occurring or gene-engineered T cells, it is critical to improve our understanding of the molecular mechanisms underlying CD8+ T cell homeostasis, fate decision and differentiation. Such knowledge has important bearing on rational design of prophylactic vaccines and immunotherapy to treat viral infections and cancers. Transcriptional and epigenetic regulation represents an important research front in CD8+ T cell biology. A plethora of factors have been extensively investigated for their capacity of controlling CD8+ T cell activity. It remains a major knowledge gap on how the actions of the CD8+ regulatory factors are orchestrated within the framework of three-dimensional (3D) genome organization. Our research goal is to uncover the less-charted regulatory functions of chromatin architecture in programming CD8+ T cell homeostasis and differentiation. The specific aims are as follows: Aim 1. To investigate Tcf1/Lef1 cooperativity with CTCF and Stat5 to promote CD8+ homoeostasis. Homeostatic cytokines (IL-7 and IL-15) and Stat5 pathway have an established central role in maintaining CD8+ T cell pool size. We will use unbiased systems biology approaches to determine the interplay of Tcf1/Lef1, CTCF and Stat5 on the levels of genomic elements and 3D genomic topology. These studies will place the dogmatic Stat5 pathway within the framework of 3D genome organized by Tcf1/Lef1 and CTCF, providing architectural basis for regulation of CD8+ homeostasis. Aim 2. To investigate the requirements for CTCF in CD8+ T cell-mediated anti-viral/tumor immunity. Memory CD8+ T cells, especially the CD62L+ central memory T (Tcm) cells, provide heightened protection against the same pathogen. We will combine high-resolution HiChIP and state-of-the-art functional assays to establish the causative link between CTCF-anchored chromatin interactions and CD8+ T cell functional output. Using inducible expression of chimeric antigen receptor (CAR) in naïve CD8+ and Tcm cells, we will further discern the intrinsic requirements for CTCF in differentiation of tumor-infiltrating CAR-T cells. This proposal will mechanistically elucidate the dynamic interplay of genome organizers and chromatin architecture in programming CD8+ T cell homeostasis and differentiation in anti-viral and anti-tumor immunity. These efforts may lead to paradigm-shifting advances in scientific knowledge, and provide novel insights into devising more effective vaccines and therapeutics for infectious diseases and cancers.

CD 8 + T淋巴细胞是建立保护性细胞免疫应答的重要参与者， 病原体和恶性转化的细胞。为了维持免疫活性，初始CD 8 + T细胞池必须 保持稳定的规模。在活化后，幼稚CD 8 + T细胞分化为细胞毒性效应细胞， 记忆细胞，清除病原体，并提供长期保护。来临 使用天然存在的或基因工程改造的T细胞的过继细胞疗法的已证实的功效， 对于提高我们对CD 8 + T细胞稳态的分子机制的理解至关重要， 决策与差异化。这些知识对预防性疫苗的合理设计具有重要意义 和免疫疗法来治疗病毒感染和癌症。 转录和表观遗传调控代表了CD 8 + T细胞生物学的重要研究前沿。一 大量的因子已经被广泛研究了它们控制CD 8 + T细胞活性的能力。它 仍然是一个主要的知识差距，如何在CD 8+调节因子的行动是精心策划的， 三维（3D）基因组组织的框架。我们的研究目标是揭示 染色质结构在编程CD 8 + T细胞稳态和分化中的调节功能。的 具体目标如下： 目标1.探讨Tcf 1/Lef 1协同CTCF和Stat 5促进CD 8+稳态的作用。 稳态细胞因子（IL-7和IL-15）和Stat 5通路在维持细胞内的免疫应答中具有确定的中心作用。 CD 8 + T细胞池大小。我们将使用无偏见的系统生物学方法来确定 Tcf 1/Lef 1、CTCF和Stat 5在基因组元件和三维基因组拓扑结构水平上的差异。这些研究将 将经典的Stat 5途径置于由Tcf 1/Lef 1和CTCF组织的3D基因组框架内， 为调节CD 8+稳态提供了结构基础。 目标2.探讨CD 8 + T细胞介导的抗病毒/肿瘤免疫对CTCF的需求。 记忆性CD 8 + T细胞，特别是CD 62 L+中枢记忆性T（Tcm）细胞，提供了增强的保护作用。 对抗相同的病原体我们将联合收割机结合高分辨率HiChIP和最先进的功能分析， 建立CTCF锚定的染色质相互作用和CD 8 + T细胞功能输出之间的因果关系。 利用嵌合抗原受体（CAR）在幼稚CD 8+和Tcm细胞中的诱导表达，我们将进一步研究嵌合抗原受体（CAR）的表达。 识别CTCF在肿瘤浸润性CAR-T细胞分化中的内在需求。 这一建议将机械地阐明基因组组织者和染色质的动态相互作用 在抗病毒和抗肿瘤免疫中编程CD 8 + T细胞稳态和分化的结构。 这些努力可能会导致科学知识的范式转变进步，并提供新的见解， 为传染病和癌症设计更有效的疫苗和治疗方法。