Transcriptional Control of Natural Killer Cell Development

项目概要/摘要 自然杀伤细胞（NK）是CD 8 T细胞的先天对应物，具有免疫原性。 能够迅速杀死病毒感染的细胞和癌细胞，并产生促炎症反应， 细胞因子（IFNγ、TNF）。这些功能属性使NK细胞成为一个有吸引力的靶点， 针对多种类型癌症的免疫疗法，并且它们已被证明可用于 移植物抗白血病然而，需要适当调节NK细胞功能， 避免自身免疫、免疫缺陷和NK细胞转化。因此，我们认为， 了解NK细胞的数量和功能是如何调节的， NK细胞作为根除疾病的治疗剂的有效用途。成熟 NK细胞群体由多个表型不同的亚群组成， 独特的功能。成熟NK细胞（mNK 1）亚群，具有CD 27 + CD 11b- 表型，维持细胞毒性效应池（CD 27-CD 11b+）以及产生 “记忆”NK细胞。我们的工作旨在了解转录基础， 维持mNK 1群体及其控制机制 分化和细胞因子反应性。在本研究中，我们将检验以下假设： E蛋白转录因子诱导一个转录程序， CD 27 + CD 11b-前体群体，并且该程序在效应子期间是ID 2 成熟我们还将检验转录因子ETS 1 与E蛋白和E蛋白靶点协同控制mNK 1分化， 细胞因子诱导的活化。这项工作将为理解 控制NK细胞数量和功能的机制， 转录网络，可以被操纵来控制这些细胞的功能， 正常和疾病状态。

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.