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

自然杀伤细胞（NK）是一种淋巴细胞群，为我们抵御入侵的微生物和异常细胞提供了第一道防线。NK细胞可以通过受体识别靶细胞、细胞因子或树突状细胞（DC）在其微环境中被激活。每个特定效应NK功能调控的分子机制仍有待确定。我的NSERC研究项目旨在了解在微环境中发现的因子如何调节nk细胞的发育、招募和特定的效应功能。******在之前的资助周期中，我们与我的HQPs一起建立了两个平台来研究NKRP1b/d-Ocil-SHP-1受体信号传导轴的操纵如何影响nk细胞靶标识别。我们发现Helios （Ikaros家族的一个转录因子）的表达水平调节nk诱导的IFN-？感染模型中的反应。我们重点研究了在不同微生物刺激下由DC产生的微环境的NK-DC串扰。我们建立了一个新的基于微流体的平台来支持NK-DC串扰中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，其重点是研究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，旨在描述短期目标，nk细胞或DC水平的特定刺激如何对nk细胞迁移进行差异调节（主题1）；Ocil on DC如何调节NK-DC串音（主题2）中活化NK细胞和DC细胞（如主题1所述）的效应功能（细胞毒性和细胞因子产生）；Ikaros转录因子家族成员的表达水平如何有助于在主题1和2中定义的NK-DC串扰条件下nk细胞迁移和效应器功能的差异调节（主题3）。长期目标是研究这些转录因子的信号网络和作用，这些转录因子是我们在短期目标中观察到的差异调节的基础。长期愿景是建立一个路线图，说明这些因素如何在确定的微环境中发育NK细胞和成熟（终末分化）NK细胞中起作用。该研究项目的新颖性和所涉及的尖端技术将为HQP（2名研究生和5名本科生）的培养创造丰富的环境。**

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). **