Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive immunity. NK cells distinguish normal from aberrant cells largely via killer cell immunoglobulin-like receptors (KIR). Despite high homology between KIR genes, individual NK cells express distinct numbers and combinations of clonally-restricted KIR (crKIR) genes. In contrast to crKIR, KIR2DL4 is expressed by all NK cells, preceding crKIR expression during NK development. The long-range goal is to use NK cells as effective treatments of cancer and infectious diseases. As the next logical step toward that goal, the current objectives are to further characterize KIR expression control in normal physiology and during epigenetic therapy of lymphoma and myelodysplastic syndrome. The rationale for the proposed research is that once KIR gene regulation is better understood, then KIR expression can be manipulated to make effective NK cells reagents in immunotherapy of cancer and infectious diseases. In this proposal, 2DL4 and crKIR promoters will be investigated, with special attention to mechanisms that overcome DNA methylation and repressive chromatin. Because so little is known about how lymphocyte-specific gene expression is influenced by cancer and by epigenetic therapy, we will study how DNA methylation and histone deacetylase inhibitor drugs affect KIR promoter methylation, KIR expression, and NK cell activation in myelodysplastic syndrome and lymphoma patients. This work may explain why NK function is poor in cancer patients and might suggest strategies for boosting immunity in these patients. We will catalog NK cell microRNA expression and their target mRNAs and we will investigate the microRNA mechanisms that regulate """"""""dangerous"""""""" cytotoxic NK cells and """"""""unlicensed"""""""" inhibitory receptor- negative NK cells. This will provide the basic information needed for future studies on control of NK developmental decisions in health and disease. This study will 1) develop a clear understanding of the multiple layers of regulation that control the initiation and maintenance of KIR expression;2) establish for the first time how epigenetic therapy affects nonmalignant human lymphocyte gene expression and function in vivo;and 3) reveal NK-specific microRNA patterns and elucidate how they control mRNA targets to regulate NK development and set NK cell activation thresholds. These results will be highly significant, because they will be essential for understanding how NK cells distinguish normal from aberrant cells. Such an understanding will suggest new ways to manipulate NK cells in the therapy of cancer and infectious diseases.

Public Health Relevance

Natural killer (NK) cells kill infected and malignant cells and direct subsequent adaptive immunity. The long-range goal is to use NK cells as effective treatments of cancer and infectious diseases. As the next logical step toward that goal, the current objectives are to further characterize NK gene expression control in normal physiology and in cancers and pre-cancers, such as lymphoma and myelodysplastic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
4R01AI050656-08
Application #
8224060
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Miller, Lara R
Project Start
2001-12-01
Project End
2013-08-31
Budget Start
2011-09-23
Budget End
2012-08-31
Support Year
8
Fiscal Year
2011
Total Cost
$367,865
Indirect Cost
Name
University of Kentucky
Department
Pathology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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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