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体，它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细胞可以通过受体识别其微环境中的靶细胞、细胞因子或树突状细胞(DC)而被激活。调节每个特定效应器NK功能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素如何调节NK细胞的发展、招募和特定的效应功能(S)。*在上一个资金周期中，我们与我的HQP一起建立了两个平台，以研究NKRP1b/d-Osel-SHP-1受体信号轴的操纵如何影响NK细胞靶标识别。我们发现，Ikaros家族的转录因子Helios的表达水平调节了NK诱导的干扰素？感染模型中的反应。我们重点研究了NK-DC串扰，它代表了DC在不同微生物刺激下创造的微环境。我们建立了一个新的基于微流控的平台来支持NK细胞在NK-DC串扰中迁移的详细分析。基于其中两个新发现，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)。我描述了三个相互独立但又相互关联的研究主题，旨在描绘在短期目标中，NK细胞迁移如何在NK细胞或DC水平上受到特定刺激的差异调控(主题1)；DC研究工具如何在NK-DC串扰中调节激活的NK和DC细胞的效应功能(如主题1所述)(如主题2)；在我们在主题1和主题2(主题3)中定义的NK-DC串扰条件下，Ikaros转录因子家族成员的表达水平如何有助于NK细胞迁移的不同调控和效应器功能(主题3)。长期目标是检查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不同调控的基础。长期的愿景是建立一个路线图，说明这些因素如何在特定的微环境中发育NK细胞和成熟(终末分化)NK细胞。研究项目的新颖性和涉及的尖端技术将为HQP(2名毕业生和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). **