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应答中起重要作用， 包括病毒和细菌，并形成一个重要的防御恶性转化 和转移。当NK细胞检测到来自细胞的信号不平衡时， 受体在其细胞表面，无论是抑制信号的损失或激活，通过激活 受体，包括细胞因子受体。这些信号通路的改变会影响 转录调控网络有助于NK细胞活化和效应子功能。在 目前，我们对主要转录因子的认识存在空白， 受这些信号通路的影响以及它们如何调节NK细胞功能。在R21中 应用程序，我们提出的数据支持的假设，Batf，创始成员的 AP-1家族转录因子，由NK细胞中的促炎细胞因子信号传导诱导 并影响NK细胞反应的多个方面。在目标1中，我们将检验以下假设： Batf通过以下途径调节NK细胞扩增、存活和效应子功能相关的关键基因： 在对小鼠巨细胞病毒的应答期间鉴定直接Batf靶标。在目标2中，我们 通过测试来检验Batf在不同NK细胞活化背景下发挥独特作用的假设 在NK细胞对转移性黑色素瘤的应答和实体瘤中对Batf的需求 依赖于NK细胞迁移和趋化因子产生的模型。综合来看，这些研究 将提供在不同NK细胞活化背景下对Batf的要求的广泛观点， 导致确定作为其基本功能基础的Batf目标。

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.