Defining extrinsic and intrinsic factors that differentially regulate migratory properties, cytokine/chemokine production, cytolytic function of NK cells

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Natural Killer (NK) cells are bone marrow derived cells that constitute 10-15% of blood lymphocytes. They migrate to peripheral sites to inflamed lymph nodes to exert their immune-surveillance functions. Activation of NK has been studied mostly by its established effector functions, such as cytotoxicity activity and/or signature cytokine (IFN-g, TNF) responses. Recent data from my laboratory and others, however, showed that these effector functions could be regulated independently via different signaling pathways. The underlying molecular mechanisms that regulated various NK functions i.e. migration, cytotoxicity, chemokine/cytokine in specific microenvironment remain to be defined. To understand the NK-mediated immune network that co-ordinates multiple cellular components in responses to infections, my research program pursues the identification of extrinsic factors produced by microenvironments that direct intrinsic cellular factors to regulate various effector functions of NK cells at different maturation states. Based on the published and preliminary work in my laboratory, we developed an overarching hypothesis to be tested in this proposal: Helios and other Ikaros family members represent a new class of regulatory factor that determine differential NK effector functions upon NK activations. I described 4 independent but interconnected themes of studies that aimed to delineate, in short-term goals, how extrinsic factors (such as soluble factors from Toll-like receptor activated DC, Theme 1 and rare peptides, Theme 2), intrinsic factors (such as Helios and other Ikaros family members, Theme 3) and GM-CSF (Theme 4) regulate NK cell migration, cytotoxicity and chemokine/cytokine production. Theme 1. To define the effects of extrinsic factors, produced by activated DC, on the migratory properties of NK cells. We will test the sub-hypothesis that mature DC activated by different microbial agents produce different chemokines that regulate different NK cell migratory responses. Theme 2. To determine how extrinsic factors, such as rare peptide would influence the outcome of NK-mediated immune surveillance mechanism. We will test the sub-hypothesis that NK cells are activated by a putative receptor for the recognition of non-self, rare short peptides. Theme 3. To define the contribution of intracellular factors, such as gene-regulatory molecules, Helios and other Ikaros family members in shaping the functional outcomes of NK cell activation. We will test the sub-hypothesis that the expression level of individual Ikaros family member regulates different effector NK cell functions. Theme 4. To determine the molecular mechanisms underlying the effects of GM-CSF on NK cell repulsion and other effective functions. We will test the sub-hypothesis that GM-CSF induces chemo-repulsion of NK cells via JAK2-Stats signaling. The long term vision is to build a road map of how these factors regulate NK development and specific effector function at defined maturation or activation states. The novelty of the research project and the cutting edge technologies involved will create a rich environment for the training of HQP.