Transcriptional Control of Natural Killer Cell Development

项目摘要/摘要 自然杀伤细胞(NK)是CD8 T细胞的先天对应细胞，具有 能够迅速杀死病毒感染的细胞和癌细胞并产生促炎作用 细胞因子(干扰素γ、肿瘤坏死因子)。这些功能特性使NK细胞成为有吸引力的靶点 针对多种癌症的免疫疗法，它们已被证明在 移植物抗白血病。然而，需要对NK细胞功能进行适当的调节 避免自身免疫、免疫缺陷和NK细胞转化。因此， 了解NK细胞的数量和功能是如何调节的，这对于 有效利用自然杀伤细胞作为根治疾病的治疗剂。成熟的 NK细胞群由多个表型不同的亚群组成，这些亚群 独特的功能能力。成熟NK细胞亚群(MNK1)，带有CD27 CD11b- 表型，维持细胞毒效应池(CD27-CD11b)以及生成 “记忆”NK细胞。我们的工作试图理解转录的基础 MNK1种群的维持及其控制机制 分化和细胞因子反应性。在这笔拨款中，我们将检验这一假设 E蛋白转录因子诱导一种转录程序，维持 CD27 CD11b-前体群体，该程序在效应器中为ID2 成熟。我们还将测试转录因子ETS1的假设 与E蛋白和E蛋白靶点合作控制mNK1分化和 细胞因子诱导活化。这项工作将为理解 控制NK细胞数量和功能的机制，并提供对 转录网络可以被操纵来控制这些细胞在 正常状态和患病状态。

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.