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

基本信息

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
项目类别：
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

项目摘要

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淋巴细胞是安装受保护的细胞免疫调查的重要参与者病原体和恶性转化的细胞。根据抗原挑战的性质，CD8+ T细胞为配备了一定水平的可塑性，以最大程度地减少感染或肿瘤细胞。病原体急性感染导致的清除率，记忆CD8+ T细胞长期持续存在，并提供了增强防止相同或相关的病原体，这些特征构成了预防性的基础疫苗。另一方面，由于慢性感染和癌症，抗原持久性会导致CD8+ T 细胞耗尽或功能障碍；尽管如此，耗尽的CD8+ T（Tex）细胞可以部分重新振奋，因为在最近在癌症免疫疗法中进行检查点封锁的成功。了解基于T细胞记忆和疲惫的分子电路对于完全利用细胞毒性CD8+ T细胞的电势可改善病毒或癌症的免疫力。在这个竞争性更新中应用程序，我们的目标是揭示TCF1的未知链接及其HDAC活性，并具有染色质可及性和基于染色质循环的增强剂促进剂相互作用在记忆和耗尽的CD8+ T细胞中。这具体目的如下：目的1。研究如何通过内存CD8+ T细胞对TCF1预编程如何增强的回忆响应。记忆CD8+ T细胞通过更强大的增殖和更快的激活暴露了增强的回忆响应细胞溶解活性比幼稚的T细胞。关于分子基础和分子调节剂是免疫反应增强的基础。我们假设TCF1预编程中央记忆CD8+ T细胞增强了对回忆刺激的响应能力。我们将使用公正系统生物学方法包括DNase-Seq和HIC，以定义TCF1及其HDAC活性控制染色质的可及性和循环。结合全面的功能研究，我们将深入执行解剖独特的分子布线，决定了TCM细胞增强的回忆反应。目标2。确定TCF1增强耗尽的CD8+ T细胞功能恢复的能力。最近的进步表明，慢性感染引起的Tex细胞包含一个CXCR5+TIM3 –子集干细胞样的自我更新能力，表达TCF1的水平升高。我们假设TCF1- 依赖的监管电路可用于耐用性，从而增强了Tex功能恢复。我们将测试各种慢性病毒感染和肿瘤模型中的TCF1形成和辅因子组合，并确定其影响关于染色质的可及性/循环及其与Tex细胞与有利功能输出的链接。该建议将机械阐明TCF1如何协调3D基因组来编程内存CD8+和耗尽的CD8+ T细胞以增强功能输出，并及时提供了急需的见解对传染病和癌症的更有效的疫苗和治疗。