Members of the Ikaros family of transcription factors in the regulation of natural killer-cell migrations and effector functions

自然杀伤（NK）细胞是一种淋巴细胞群，为我们提供了抵御入侵微生物和异常细胞的第一道防线。NK细胞可以通过其微环境中的靶细胞、细胞因子或树突状细胞（DC）的受体识别而被激活。每种特定效应NK功能的分子机制仍有待确定。我的NSERC研究计划旨在了解微环境中发现的因素如何调节NK细胞的发育，招募和特定的效应器功能。** 在上一个资助周期中，我们与我的HQP一起建立了两个平台来研究NKRP 1b/d-ODN-SHP-1受体信号传导轴的操纵如何影响NK细胞靶向免疫。我们发现，表达水平的太阳神（一个转录因子的Ikaros家族）调节NK诱导的IFN-？感染模型中的反应。我们专注于NK-DC串扰，其代表DC在不同微生物刺激下产生的微环境。我们建立了一个新的基于微流体的平台，以支持在NK-DC串扰中的NK细胞迁移的详细分析。基于这些新发现中的两个，我开发了一个更新应用程序，重点研究Helios及其相关家族成员如何在NK-DC串扰中调节NK细胞功能（迁移，细胞毒性，趋化因子/细胞因子的产生）。我描述了3个独立但相互关联的研究主题，其目的是在短期目标中描述NK细胞或DC水平上的特异性刺激如何差异调节NK细胞迁移（主题1）;活化的NK和DC细胞的细胞毒性和细胞因子产生（如主题1所述）在NK-DC相声（主题2）; Ikaros转录因子家族成员的表达水平如何有助于NK细胞迁移和NK细胞中效应子功能的差异调节，我们在主题1和2中定义了直流串扰条件（主题3）。长期目标是研究我们在短期目标中观察到的差异调节的信号网络和这些转录因子的作用。长期愿景是建立一个路线图，说明这些因素如何在定义的微环境中发育NK细胞和成熟（终末分化）NK细胞。该研究项目的新奇和所涉及的尖端技术将为HQP（2名研究生和5名本科生）的培训创造一个丰富的环境。**

Natural killer (NK) cells are a lymphocyte population that provides us a first line of defense against invading microbes and abnormal cells. NK cells can be activated by receptor recognition of target cells, cytokines or dendritic cells (DC) in their microenvironments. Molecular mechanisms underlying regulation of each specific effector NK function remain to be defined. My NSERC research program aims at understanding of how factors found in the microenvironments regulate NK-cell development, recruitment and specific effector function(s). ******In the previous funding cycle, together with my HQPs, we established two platforms to study how manipulations of the axis of NKRP1b/d-Ocil-SHP-1 receptor signaling affected NK-cell target recognitions. We discovered that the expression level of Helios (a transcription factor of the Ikaros family) regulated NK-induced IFN-? responses in infection models. We focused on NK-DC crosstalk that represented microenvironments created by DC under different microbial stimulations. We established a novel microfluidic-based platform to support detail analysis of NK-cell migrations in NK-DC crosstalk. Based upon two of these novel findings, I developed a renewal application with a focused objective of studying how Helios and its related family members regulate NK cell functions (migration, cytotoxicity, production of chemokines/cytokines) in NK-DC crosstalk. I described 3 independent but interconnected themes of studies that aimed to delineate, in short-term goals, how NK-cell migrations are differentially regulated by specific stimulations at the NK-cell or DC level (Theme 1); how Ocil on DC regulates effector functions (cytotoxicity and cytokine production) of activated NK and DC cells (as described in Theme 1) in the NK-DC crosstalk (Theme 2); how expression levels of the members of the Ikaros transcription factor family can contribute to the differential regulation of NK-cell migrations and effector functions in the NK-DC crosstalk conditions we defined in Themes 1 and 2 (Theme 3). Long-term goal is to examine the signaling networks and actions of these transcription factors underlying the differential regulations we observed in the short-term goals. The long-term vision is to build a road map of how these factors operate in developing NK cells and mature (terminally differentiated) NK cells in defined microenvironments. The novelty of the research project and the cutting edge technologies involved will create a rich environment for the training of HQP (2 graduates and 5 undergraduates). **