Tcf1 programs CD8 T cell responses to enhance viral and cancer immunity

Tcf1 编程 CD8 T 细胞反应以增强病毒和癌症免疫力

• 批准号: 10396568
• 负责人: Hai-Hui Xue
• 金额: $ 52.27万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396568
• 关键词: 3-Dimensional; ATAC-seq; Acute; Affect; Antigens; BLR1 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell Cycle; Cells; Chromatin; Chromatin Loop; Chronic; Communicable Diseases; DNase I hypersensitive sites sequencing; Dissection; Ectopic Expression; Enhancers; Environment; Epigenetic Process; Exhibits; Functional disorder; Funding; Generations; Genetic Transcription; Genome; Glycolysis Induction; Glycolysis Pathway; Goals; Hi-C; Histone Deacetylase; Immune response; Impairment; Infection; Knowledge; Link; Malignant - descriptor; Malignant Neoplasms; Mature T-Lymphocyte; Memory; Modeling; Modification; Molecular; Nature; Output; Pathogenicity; Pathway interactions; Phase; Phenotype; Preventive vaccine; Progress Reports; Research; Rest; Role; SELL gene; Systems Biology; T cell differentiation; T cell response; T cell transcription factor 1; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Thymocyte Development; Time; Transcriptional Regulation; Tumor Immunity; Vaccines; Viral; Viral Cancer; Virus Diseases; acute infection; antigen challenge; base; cancer immunotherapy; cell transformation; chronic infection; cofactor; cytotoxic; cytotoxic CD8 T cells; exhaust; exhaustion; functional restoration; gain of function; immune checkpoint blockade; improved; insight; neoplastic cell; pathogen; pre-clinical; programs; promoter; response; self-renewal; stem; stem cells; stem-like cell; success; transcription factor; transcriptome; transcriptomics; tumor

CD8+ T lymphocytes are essential players in mounting protective cellular immune responses against pathogens and malignantly transformed cells. Depending on the nature of antigen challenge, CD8+ T cells are equipped with certain levels of plasticity to maximize reduction of infected or tumor cells. After pathogen clearance resulting from acute infections, memory CD8+ T cells persist for long term and provide enhanced protection against the same or related pathogens, and these features constitute the basis for prophylactic vaccines. On the other hand, antigen persistence, as a result of chronic infection and cancers, causes CD8+ T cell exhaustion or dysfunction; nonetheless, the exhausted CD8+ T (Tex) cells can be partly reinvigorated, as seen in recent success of checkpoint blockade in cancer immunotherapy. Understanding molecular circuits that underlie T cell memory and exhaustion is critical for fully harnessing the potentials of cytotoxic CD8+ T cells for improving viral or cancer immunity. In this competitive renewal application, our goal is to uncover the uncharted links of Tcf1 and its HDAC activity with chromatin accessibility and chromatin looping-based enhancer-promoter interactions in memory and exhausted CD8+ T cells. The specific aims are as follows: Aim 1. To investigate how Tcf1 preprograms enhanced recall responses by memory CD8+ T cells. Memory CD8+ T cells exhibit enhanced recall response by more robust proliferation and more rapid activation of cytolytic activities than naïve T cells. A major knowledge gap remains regarding the molecular basis and molecular regulators that underlie the heightened immune response. We hypothesize that Tcf1 preprograms central memory CD8+ T cells for their enhanced responsiveness to recall stimulation. We will use unbiased systems biology approaches including DNase-seq and HiC to define how Tcf1 and its HDAC activity control chromatin accessibility and looping. Combined with comprehensive functional studies, we will perform in-depth dissection of the unique molecular wiring that dictates enhanced recall responses by Tcm cells. Aim 2. To determine the capacity of Tcf1 to enhance functional restoration of exhausted CD8+ T cells. Recent advances revealed that Tex cells elicited by chronic infection contain a CXCR5+Tim3– subset that has stem cell-like self-renewing capacity and expresses an elevated level of Tcf1. We hypothesize that Tcf1- dependent regulatory circuits can be utilized to durably enhance Tex functional restoration. We will test various Tcf1 forms and cofactor combinations in chronic viral infection and tumor models, and determine their impact on chromatin accessibility/looping and its link to favorable functional output by Tex cells. This proposal will mechanistically elucidate how Tcf1 orchestrates 3D-genome to program memory CD8+ and exhausted CD8+ T cells for enhanced functional output, and provide timely, much needed 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。根据抗原挑战的性质，CD8+T细胞是 配备一定程度的可塑性，最大限度地减少感染或肿瘤细胞。后遗症 急性感染引起的清除，记忆CD8+T细胞长期存在并提供增强 对相同或相关病原体的保护，这些特征构成了预防的基础 疫苗。另一方面，由于慢性感染和癌症导致的抗原持久性导致CD8+T细胞 细胞耗尽或功能障碍；然而，耗尽的CD8+T(TeX)细胞可以部分恢复活力，如 最近检查点封锁在癌症免疫治疗中取得了成功。 了解T细胞记忆和衰竭背后的分子电路对于充分利用 细胞毒CD8+T细胞提高病毒或癌症免疫的潜力。在这场竞争性的更新中 应用程序，我们的目标是揭示Tcf1及其HDAC活性与染色质可及性的未知联系 以及基于染色质环的增强子-启动子在记忆和耗尽的CD8+T细胞中的相互作用。这个 具体目标如下： 目的1.研究Tcf1是如何通过记忆CD8+T细胞预编码增强的回忆反应的。 记忆性CD8+T细胞通过更强劲的增殖和更快的激活显示出增强的回忆反应 比单纯T细胞具有更强的细胞溶解活性。一个主要的知识差距仍然是关于分子基础和 作为免疫反应增强基础的分子调节器。我们假设TCF1预编程序 中央记忆CD8+T细胞对回忆刺激的反应增强。我们将不偏不倚地 包括DNASE-SEQ和HIC在内的系统生物学方法来定义TCF1及其HDAC活性控制 染色质的可及性和环路。结合全面的功能研究，我们将深入进行 解剖独特的分子线路，指示中医细胞增强回忆反应。 目的2.检测Tcf1促进耗竭CD8+T细胞功能恢复的能力。 最近的研究表明，慢性感染诱导的TEX细胞含有CXCR5+TIM3-亚群，具有 干细胞样的自我更新能力，并表达高水平的Tcf1。我们假设TCF1- 可以利用依赖的调节电路来持久地增强TeX功能恢复。我们将测试各种 Tcf1在慢性病毒感染和肿瘤模型中的形式和辅因子组合，并确定它们的影响 关于染色质可及性/环路及其与TeX细胞良好功能输出的联系。 这一提议将机械地阐明Tcf1如何协调3D基因组来编程存储器CD8+和 耗尽CD8+T细胞以增强功能输出，并为设计提供及时、迫切需要的见解 针对传染病和癌症的更有效的疫苗和疗法。