Identification of BATF function and targets during NK cell activation

项目摘要 自然杀伤(NK)细胞在对细胞内病原体的免疫反应中起着至关重要的作用， 包括病毒和细菌，并形成防止恶变的重要防御措施 和转移。当NK细胞检测到信号不平衡时，它们被激活 细胞表面的受体，要么是抑制信号的丧失，要么是通过激活而激活 受体包括细胞因子受体。这些信号通路的改变会影响 有助于NK细胞激活和效应器功能的转录调控网络。在… 目前，我们对主要转录因子的了解存在差距，这些转录因子是 受到这些信号通路的影响，以及它们如何调节NK细胞的功能。在此R21中 应用程序中，我们提供了数据来支持这样的假设，即BATF是 AP-1家族转录因子，由NK细胞中的促炎细胞因子信号诱导 并影响NK细胞反应的多个方面。在目标1中，我们将检验假设 BATF通过以下途径调节与NK细胞增殖、存活和效应器功能有关的关键基因 在对小鼠巨细胞病毒的应答中识别BATF的直接靶点。在目标2中，我们将 通过测试验证BATF在不同NK细胞激活环境中发挥独特作用的假设 转移性黑色素瘤和实体瘤NK细胞对BATF的需求 依赖NK细胞迁移和趋化因子产生的模型。总而言之，这些研究 将提供在不同的NK细胞激活环境中对BATF的要求的广泛视角，以及 导致确定BATF的目标，这是其基本职能的基础。

Project Summary Natural killer (NK) cells play essential roles in the immune response to intracellular pathogens, including viruses and bacteria, and form an important defense against malignant transformation and metastasis. NK cells are activated when they detect an imbalance in the signals from receptors on their cell surface, either a loss of inhibitory signals or activation through activating receptors including cytokine receptors. Alterations in these signaling pathways impact the transcriptional regulatory networks that contribute to NK cell activation and effector function. At the present time there is a gap in our knowledge of the major transcription factors that are impacted by these signaling pathways and how they modulate NK cell function. In this R21 application, we present data to support the hypothesis that Batf, the founding member of the AP-1 family of transcription factors, is induced by proinflammatory cytokine signaling in NK cells and impacts multiple aspects of the NK cell response. In aim 1, we will test the hypothesis that Batf regulates key genes involved in NK cell expansion, survival, and effector function by identifying direct Batf targets during the response to mouse cytomegalovirus. In aim 2, we will test the hypothesis that Batf plays unique roles in different NK cell activating contexts by testing the requirement for Batf in the NK cell response to metastatic melanoma and in a solid tumor model that relies on NK cell migration and chemokine production. Taken together, these studies will provide a broad view of the requirements for Batf in distinct NK cell activation contexts and lead to the identification of Batf targets that underlie its essential functions.