Transcriptional Control of Natural Killer Cell Development

自然杀伤细胞发育的转录控制

• 批准号: 10540688
• 负责人: BARBARA L. KEE
• 金额: $ 48.6万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540688
• 关键词: ATAC-seq; Activities of Daily Living; Address; Alleles; Applications Grants; Autoimmunity; B-Lymphocytes; Biological Assay; Biotinylation; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cell Count; Cell Differentiation process; Cell Line; Cell Maintenance; Cell physiology; Cells; ChIP-seq; Collaborations; Data; Development; Disease; E protein; ETS1 gene; Endowment; Enhancers; Essential Genes; Foundations; Future; Gene Expression Profiling; Genes; Genetic Transcription; Goals; Grant; Homeostasis; ID2 gene; ITGAM gene; Immune; Immunotherapy; Inflammatory; Interferon Type II; Interleukin-15; Luciferases; Maintenance; Malignant - descriptor; Mediating; Memory; Mus; Mutagenesis; Mutation; Natural Killer Cells; Phenotype; Play; Population; Production; Regulation; Regulatory Element; Repression; Role; T-Cell Development; TNF gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Transcriptional Regulation; Virus; Work; cancer cell; cancer type; cell transformation; cytokine; cytotoxic; experimental study; graft vs leukemia effect; immune checkpoint blockade; improved; in vivo; inhibitor; insight; leukemic transformation; novel; programs; rapid detection; response; transcription factor; tumor

Project Summary/Abstract Natural killer cells (NK) are the innate counterpart to CD8 T cells, endowed with the ability to rapidly kill virus-infected cells and cancer cells and produce proinflammatory cytokines (IFNγ, TNF). These functional attributes make NK cells an attractive target for immunotherapy against multiple types of cancer, and they have been proven useful in graft versus leukemia. However, appropriate regulation of NK cell function is needed to avoid autoimmunity, immune deficiency, and NK cell transformation. Therefore, understanding how NK cell number and function are regulated is essential for the effective use of NK cells as therapeutic agents for eradication of disease. The mature NK cell population is composed of multiple phenotypically distinct subsets that have unique functional abilities. A subset of mature NK cells (mNK1), with a CD27+CD11b- phenotype, maintains the cytotoxic effector pool (CD27-CD11b+) as well as generating “memory” NK cells. Our work seeks to understand the transcriptional basis for maintenance of the mNK1 population and the mechanisms controlling their differentiation and cytokine responsiveness. In this grant we will test the hypothesis that E protein transcription factors induce a transcriptional program that maintains the CD27+CD11b- precursor population and that this program is ID2 during effector maturation. We will also test the hypothesis that the transcription factor ETS1 collaborates with E proteins and E protein targets to control mNK1 differentiation and cytokine induced activation. This work will provide a foundation for understanding the mechanisms that control NK cell number and function and provide insight into the transcriptional network that can be manipulated to control the function of these cells in normal and diseased states.

项目摘要/摘要 天然杀伤细胞（NK）是与CD8 T细胞的先天对应物，并具有 能够快速杀死病毒感染的细胞和癌细胞并产生促炎性的能力 细胞因子（IFNγ，TNF）。这些功能属性使NK单元成为吸引人的目标 针对多种癌症的免疫疗法，已被证明对 移植与白血病。但是，需要对NK细胞功能进行适当的调节 避免自身免疫性，免疫缺陷和NK细胞转化。所以， 了解如何调节NK单元格数和功能对于 有效地将NK细胞用作治疗剂用于疾病的放疗。成熟 NK细胞群由多种表型不同的子集组成 独特的功能能力。成熟的NK细胞的子集（MNK1），带有CD27+CD11b- 表型，维持细胞毒性效应子池（CD27-CD11B+）以及生成 “内存” NK单元。我们的工作旨在了解转录基础 维持MNK1人群及其控制的机制 分化和细胞因子反应。在这笔赠款中，我们将检验以下假设 E蛋白转录因子会影响一项转录程序，以维持 CD27+CD11B-前体人群，该程序在效应器期间是ID2 成熟。我们还将测试转录因子ETS1的假设1 与E蛋白和E蛋白靶标合作，以控制MNK1分化和 细胞因子诱导的激活。这项工作将为理解 控制NK单元格数和功能的机制，并提供有关 可以操纵以控制这些单元功能的转录网络 正常和患病状态。

项目成果

Transcription factor ID2 prevents E proteins from enforcing a naïve T lymphocyte gene program during NK cell development.

• DOI: 10.1126/sciimmunol.aao2139
• 发表时间: 2018-04-27
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Zook EC;Li ZY;Xu Y;de Pooter RF;Verykokakis M;Beaulieu A;Lasorella A;Maienschein-Cline M;Sun JC;Sigvardsson M;Kee BL
• 通讯作者: Kee BL

The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation.

• DOI: 10.1084/jem.20141849
• 发表时间: 2015-05-04
• 期刊: The Journal of experimental medicine
• 作者: Carr T;Krishnamoorthy V;Yu S;Xue HH;Kee BL;Verykokakis M
• 通讯作者: Verykokakis M

The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2.

• DOI: 10.1084/jem.20150851
• 发表时间: 2016-05-02
• 期刊: The Journal of experimental medicine
• 作者: Zook EC;Ramirez K;Guo X;van der Voort G;Sigvardsson M;Svensson EC;Fu YX;Kee BL
• 通讯作者: Kee BL

E Protein Transcription Factors as Suppressors of T Lymphocyte Acute Lymphoblastic Leukemia.

• DOI: 10.3389/fimmu.2022.885144
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

ID'ing innate and innate-like lymphoid cells.

• DOI: 10.1111/imr.12203
• 发表时间: 2014-09
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Verykokakis M;Zook EC;Kee BL
• 通讯作者: Kee BL