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

点击翻译按钮获取中文摘要

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).