Delineating novel functions of Semaphorin 3E in regulating natural killer cell biology

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Natural killer (NK) cells are important immune cells that regulate innate immunity. NK cells are activated by receptor recognition of target cells, cytokines or dendritic cells (DC) in their microenvironments. How specific factor(s) found in their local microenvironments regulate NK cell biology remains to be defined. My NSERC-funded research program seeks to achieve a molecular understanding of how factors found in microenvironments regulate NK-cell development, recruitment and/or NK cell effector functions. One of the key findings I have obtained in the last funding cycle is the novel role of Semaphorin 3E (Sema3E), a protein originally identified for its roles in neurodevelopment, in regulating NK-cell migration in the NK-DC crosstalk. The objective of my current NSERC-DG proposal is to delineate novel functions of the Sema3E/PlexinD1 pathway in regulating various aspects of NK cell biology under the experimental microenvironments we defined by cytokines and NK-DC crosstalk. Global Hypothesis: The Sema3E/Plexin D1 axis is a novel signaling pathway that regulates NK cell maturation, effector functions (cytotoxicity, cytokine production) and/or migratory properties. Specific Objectives: 1. To examine the maturation program of NK cells in Sema3E deficient mice. I will quantify immature and mature NK cell subsets in spleen and bone marrow. I will examine proliferation, apoptosis, exhaustion phenotypes and cell cycle in the ex vivo NK and activated NK cells. 2. To delineate molecular mechanism underlying Sema3E regulation of NK cell functions. I will determine whether Sema3E deficiency impacts migratory properties of NK cells under different defined microenvironments in vitro. I will elucidate signaling networks that are impacted by Sema3E deficiency, and how they affect NK cell effector functions. 3. To determine whether Sema3E deficiency directly regulate NK cell development and functions via the cognate Sema3E receptor (Plexin D1) on NK cells. I will use recombinant Sema3E in in vitro NK cultures to examine whether direct activation of the PlexinD1 receptor on NK cells modulates NK cell functions. I will create a novel NK specific Plexin D1 KO mouse model to examine NK cell development and functions in our established assays. Significance: Discoveries from this proposed work will advance our understanding of how this novel Sema3E/PlexinD1 pathway regulates NK cell lymphocyte biology in both sexes, and provide new insights into how this and other novel pathways operate in specific microenvironments. The novelty of the research projects covered in this cycle, the Kung laboratory that supports equity, diversity and inclusion in research, the cutting edge technologies and the experimental approaches involved will train and prepare my HQP well to lead research projects in either academic or private sectors.