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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

基本信息

批准号：
10708935
负责人：
Weiqun Peng
金额：
$ 52.3万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10708935
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 Infiltration Interleukin-15 Knowledge Link Malignant - descriptor Malignant Neoplasms Mature T-Lymphocyte Mediating Memory Molecular Molecular Analysis Multiomic Data Nature Output Pathway interactions Pattern Preventive vaccine Progress Reports Proliferating Regulation Research Research Design Resolution Role SELL gene Shapes 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

项目摘要

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.

CD8+T淋巴细胞在提高保护性细胞免疫应答中起重要作用病原体和恶性转化细胞。为了维持免疫能力，天真的CD8+T细胞池必须保持稳定的大小。激活后，原始CD8+T细胞分化为细胞毒效应细胞，并分别清除病原体和提供更强的长期保护的记忆细胞。随着时代的到来在使用自然产生的或基因工程的T细胞进行过继细胞治疗的显示效果中，它是对提高我们对CD8+T细胞动态平衡的分子机制的理解至关重要决策和差异化。这些认识对预防性疫苗的合理设计具有重要意义。以及治疗病毒感染和癌症的免疫疗法。转录和表观遗传调控是CD8+T细胞生物学的一个重要研究前沿。一个过多的因子被广泛研究为它们控制CD8+T细胞活性的能力。它对于CD8+监管因素的行动是如何在三维(3D)基因组组织框架。我们的研究目标是发现那些鲜为人知的东西染色质结构在编程CD8+T细胞内稳态和分化中的调节功能。这个具体目标如下：目的1.探讨Tcf1/Lef1与CTCFs和Stat5在促进CD8+稳态中的协同作用。动态平衡细胞因子(IL-7和IL-15)和Stat5途径在维持 CD8+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 Tcf1/Lef1、CTCF和Stat5在基因组元件和三维基因组拓扑水平上的差异。这些研究将将教条性的Stat5通路置于由Tcf1/Lef1和CTCF组织的3D基因组框架内，为CD8+动态平衡的调控提供了构筑基础。目的2.探讨CD8+T细胞介导的抗病毒/肿瘤免疫对CTCF的要求。记忆性CD8+T细胞，特别是CD62L+中央记忆性T(Tcm)细胞，提供更强的保护对抗相同的病原体。我们将结合高分辨率HiChIP和最先进的功能分析来建立CTCF锚定的染色质相互作用和CD8+T细胞功能输出之间的因果联系。利用嵌合抗原受体(CAR)在初始CD8+细胞和中医细胞中的可诱导表达，我们将进一步明确CTCF在肿瘤浸润性CAR-T细胞分化中的内在要求。这一提议将机械地阐明基因组组织者和染色质之间的动态相互作用在抗病毒和抗肿瘤免疫中编程CD8+T细胞的稳态和分化的架构。这些努力可能导致科学知识的范式转变进步，并为为传染病和癌症设计更有效的疫苗和疗法。