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: 10611882
• 负责人: Hai-Hui Xue
• 金额: $ 51.66万
• 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/10611882
• 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; Proliferating; 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; Transcriptional Regulation; Tumor Immunity; Vaccines; Viral; Virus Diseases; acute infection; antigen challenge; 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 淋巴细胞是发起保护性细胞免疫反应的重要参与者 根据抗原攻击的性质，CD8+ T 细胞是病原体和恶性转化细胞。 具有一定程度的可塑性，最大限度地减少感染或肿瘤细胞后的病原体。 清除急性感染引起的记忆 CD8+ T 细胞长期存在并提供增强的 针对相同或相关病原体的保护作用，这些特征构成了预防性治疗的基础 另一方面，慢性感染和癌症导致的抗原持续存在会导致 CD8+ T。 细胞耗竭或功能障碍；然而，耗竭的 CD8+ T (Tex) 细胞可以部分恢复活力，如 最近在癌症免疫治疗中检查点封锁的成功就可见一斑。 了解 T 细胞记忆和耗竭背后的分子回路对于充分利用 T 细胞记忆和耗竭至关重要。 细胞毒性 CD8+ T 细胞在这种竞争性更新中改善病毒或癌症免疫力的潜力。 应用程序中，我们的目标是揭示 Tcf1 及其 HDAC 活性与染色质可及性之间的未知联系 记忆和耗竭 CD8+ T 细胞中基于染色质环的增强子-启动子相互作用。 具体目标如下： 目标 1. 研究 Tcf1 如何预编程增强记忆 CD8+ T 细胞的回忆反应。 记忆 CD8+ T 细胞通过更强劲的增殖和更快速的激活表现出增强的回忆反应 与初始 T 细胞相比，细胞溶解活性的主要知识差距仍然存在。 我们勇敢地承认 Tcf1 是哮喘免疫反应的分子调节因子。 中枢记忆 CD8+ T 细胞对回忆刺激的反应能力增强。 系统生物学方法，包括 DNase-seq 和 HiC，用于定义 Tcf1 及其 HDAC 活性控制 结合染色质可及性和循环的综合功能研究，我们将进行深入的研究。 剖析决定 Tcm 细胞增强记忆反应的独特分子线路。 目标 2. 确定 Tcf1 增强耗竭 CD8+ T 细胞功能恢复的能力。 最近的进展表明，慢性感染引起的 Tex 细胞含有 CXCR5+Tim3– 子集，该子集具有 干细胞样自我更新能力并表达升高水平的 Tcf1。 相关调节电路可用于持久增强 Tex 功能恢复。 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 染色质可及性/循环及其与 Tex 细胞有利功能输出的联系。 该提案将机械地阐明 Tcf1 如何协调 3D 基因组来编程内存 CD8+ 和 耗尽 CD8+ T 细胞以增强功能输出，并为设计提供及时、急需的见解 针对传染病和癌症的更有效的疫苗和疗法。

项目成果

Polymicrobial sepsis influences NK-cell-mediated immunity by diminishing NK-cell-intrinsic receptor-mediated effector responses to viral ligands or infections.

多种微生物脓毒症通过减少 NK 细胞固有受体介导的对病毒配体或感染的效应反应来影响 NK 细胞介导的免疫。

• 发表时间: 2018
• 影响因子: 6.7
• 作者: Jensen, Isaac J;Winborn, Christina S;Fosdick, Micaela G;Shao, Peng;Tremblay, Mikaela M;Shan, Qiang;Tripathy, Sandeep Kumar;Snyder, Christopher M;Xue, Hai;Griffith, Thomas S;Houtman, Jon C;Badovinac, Vladimir P
• 通讯作者: Badovinac, Vladimir P

TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow.

TCF-1 上调可识别骨髓中的早期先天淋巴祖细胞。

• 发表时间: 2015-10
• 影响因子: 30.5
• 作者: Yang, Qi;Li, Fengyin;Harly, Christelle;Xing, Shaojun;Ye, Longyun;Xia, Xuefeng;Wang, Haikun;Wang, Xinxin;Yu, Shuyang;Zhou, Xinyuan;Cam, Maggie;Xue, Hai;Bhandoola, Avinash
• 通讯作者: Bhandoola, Avinash

Tcf1 and Lef1 are required for the immunosuppressive function of regulatory T cells.

Tcf1 和 Lef1 是调节性 T 细胞的免疫抑制功能所必需的。

• 发表时间: 2019
• 作者: Xing, Shaojun;Gai, Kexin;Li, Xiang;Shao, Peng;Zeng, Zhouhao;Zhao, Xudong;Zhao, Xin;Chen, Xia;Paradee, William J;Meyerholz, David K;Peng, Weiqun;Xue, Hai
• 通讯作者: Xue, Hai

Publisher Correction: Tcf1 preprograms the mobilization of glycolysis in central memory CD8+ T cells during recall responses.

出版商更正：Tcf1 在回忆反应期间预编程中央记忆 CD8 T 细胞中糖酵解的动员。

• 发表时间: 2022-05
• 影响因子: 30.5
• 作者: Shan, Qiang;Hu, Shengen Shawn;Zhu, Shaoqi;Chen, Xia;Badovinac, Vladimir P;Peng, Weiqun;Zang, Chongzhi;Xue, Hai
• 通讯作者: Xue, Hai

Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses.

mTOR 复合物 1 和 2 对于滤泡辅助 T 细胞分化和生发中心反应的关键作用。

• 发表时间: 2016
• 影响因子: 7.7
• 作者: Yang, Jialong;Lin, Xingguang;Pan, Yun;Wang, Jinli;Chen, Pengcheng;Huang, Hongxiang;Xue, Hai;Gao, Jimin;Zhong, Xiao
• 通讯作者: Zhong, Xiao