Natural killer (NK) cells use killer cell immunoglobulin-like receptors (KIR) to distinguish normal cells from infected and malignant cells. NK cells express an apparently random assortment of KIR genes. Our LONG RANGE GOAL is to use NK cells to treat cancer and infectious diseases. Our CURRENT OBJECTIVE is to identify how developing NK cells initiate and then maintain selective KIR gene expression. Supported by strong preliminary data, our CENTRAL HYPOTHESIS is that promoter methylation controls locus-specific and allele-specific KIR gene expression. The RATIONALE for the proposed research is that understanding KIR gene regulation could lead to effective immunotherapy of cancer and infectious diseases. Furthermore, our research will test the central paradigm of tissue-specific gene expression. The proposed research is a COLLABORATION between investigators at two universities. The principal investigator has an established record of research in NK ceils, immune recognition of HLA class I molecules, and molecular biology. The other investigators are leaders in gene expression control and in human NK cell development. The collaboration will produce a synergistic effect that is not easily matched by a single investigator.
Our SPECIFIC AIMS are to 1. Test the molecular mechanisms of KIR gene expression control. 2. Define cis acting elements and trans-acting factors that control KIR gene expression. 3. Elucidate how developing NK cells initiate selective KIR gene expression. Our approach is INNOVATIVE. We have produced unique new data and we will combine several cutting-edge research techniques to rigorously test our hypotheses. It is our EXPECTATION that 1) we will develop a clear understanding of how NK cells maintain stable KIR expression; 2) we will define several important cis-acting elements and trans-acting factors that regulate KIR transcription; 3) we will identify what signals developing NK cells use to initiate KIR gene expression. Our results will be highly SIGNFICANT, because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Of broader significance, elucidation of KIR gene expression control will provide an important model for gene choice in development and offer insights into birth defects and cancer.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Immunology Study Section (EI)
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Winter, David B
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University of Kentucky
Schools of Medicine
United States
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Lutz, Charles T (2014) Human leukocyte antigen Bw4 and Bw6 epitopes recognized by antibodies and natural killer cells. Curr Opin Organ Transplant 19:436-41
Presnell, S R; Chan, H-W; Zhang, L et al. (2013) IL-2/IL-15 activate the human clonally restricted KIR3DL1 reverse promoter. Genes Immun 14:107-14
Segerstrom, Suzanne C; Al-Attar, Ahmad; Lutz, Charles T (2012) Psychosocial resources, aging, and natural killer cell terminal maturity. Psychol Aging 27:892-902
Lutz, Charles T; Quinn, LeBris S (2012) Sarcopenia, obesity, and natural killer cell immune senescence in aging: altered cytokine levels as a common mechanism. Aging (Albany NY) 4:535-46
Presnell, Steven R; Zhang, Lei; Chlebowy, Corrin N et al. (2012) Differential transcription factor use by the KIR2DL4 promoter under constitutive and IL-2/15-treated conditions. J Immunol 188:4394-404
Cichocki, Frank; Felices, Martin; McCullar, Valarie et al. (2011) Cutting edge: microRNA-181 promotes human NK cell development by regulating Notch signaling. J Immunol 187:6171-5
Lutz, Charles T; Karapetyan, Anush; Al-Attar, Ahmad et al. (2011) Human NK cells proliferate and die in vivo more rapidly than T cells in healthy young and elderly adults. J Immunol 186:4590-8
Butler, James E; Moore, Mikel B; Presnell, Steven R et al. (2009) Proteasome regulation of ULBP1 transcription. J Immunol 182:6600-9
Binyamin, Liat; Alpaugh, R Katherine; Hughes, Tracey L et al. (2008) Blocking NK cell inhibitory self-recognition promotes antibody-dependent cellular cytotoxicity in a model of anti-lymphoma therapy. J Immunol 180:6392-401
McCullar, Valarie; Oostendorp, Robert; Panoskaltsis-Mortari, Angela et al. (2008) Mouse fetal and embryonic liver cells differentiate human umbilical cord blood progenitors into CD56-negative natural killer cell precursors in the absence of interleukin-15. Exp Hematol 36:598-608

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