Charles T. Lutz, M.D., Ph.D.
Professor
Doctoral Studies: University of Chicago.
Postdoctoral: Washington University, St. Louis.
Research Statement
As a bridge between the innate and adaptive immune systems, natural killer (NK) lymphocytes recognize aberrant cells early in infection and tumor development. NK cells kill aberrant cells and secrete cytokines to orchestrate subsequent adaptive immune responses. We wish to understand how these important lymphocytes are regulated and how they discriminate “self” from “nonself.”
1. Regulation of KIR gene expression. NK cells use killer immunoglobulin-like receptors (KIR) and CD94/NKG2A receptors to recognize aberrant cells. These receptors bind to MHC class I molecules, which are downregulated on cancer and infected cells. KIR genes are expressed in a random fashion by NK cells. We showed that KIR expression is allele-specific and is controlled by promoter DNA methylation. We have recently completed investigating promoter differences between clonally-restricted KIR genes and the KIR2DL4 gene that is expressed in all NK cells. Heavy reliance on a single transcription factor, Runx-3, maintains low-level KIR2DL4 transcription in mature CD56dim NK cells. A juxtaposed KIR2DL4 Ets/Runx promoter site is sensitive to IL-15 and IL-2 signaling and drives higher expression in cytokine-stimulated immature CD56bright NK cells. We are investigating the interplay between transcription factors and epigenetic control of KIR expression in myelodysplastic syndrome and lymphoma patients treated with DNA methylation inhibitors.
2. MicroRNA regulation of NK cell maturation and activation. We have discovered several miRNAs that are differentially expressed in human NK cells. Two of these, miR-181a and miR-181b, control NK cell activation and NK cell maturation, in part by regulating early NK cell signaling. We are investigating the role of other miRNAs in NK cell activation and development.
3. Effects of aging on NK cell function. Immune function declines with normal aging, yet peripheral blood NK cells are elevated in healthy elderly people, both in relative and absolute numbers. We found that fewer NK cells express CD94/NKG2A with aging due to decreased percentages of the immature CD56bright NK population in elderly people. Despite this, turnover of each NK subset was similar in young and elderly subjects. Because NK cells are sentinel predictors of death in the elderly, we are initiating investigation of how other health measures affect NK cells in aging humans.
4. Interaction between skeletal muscle, adipose tissue, and NK cells. We are investigating the novel hypothesis that inflammatory cytokines made by visceral adipose tissue and IL-15 made by skeletal muscle influence NK cell turnover and activity in aging humans.
Grants
R01 AI050656-08, Molecular Mechanisms Controlling NK Cell Receptor Expression, 08/01/09 to 07/31/13. Annual Direct Costs, $250,000. Principal Investigator: Charles T. Lutz.
R21 AG040542, Muscle, Fat and NK Lymphocytes in Aging. Annual Direct Costs, $150,000. Principal Investigator: Charles T. Lutz, 08/01/12 to 07/31/14.
2 R01 AG026307-06, Self-Regulation, Immunological Aging, and Health in Older Adults, 7/1/2012-6/30/2017, Annual Direct Costs, $379,882. Principal Investigator: Suzanne C. Segerstrom.
Select Recent Publications
Butler JE, Moore MB, Chan W-C, Presnell SR, Chalupny NJ and Lutz CT. 2009. Proteasome regulation of ULBP1 transcription. J. Immunol. 182: 6600. {PubMed ID 19414815}
Lutz CT, Karapetyan A, Al-Attar A, Shelton BJ, Holt KJ, Tucker JH and Presnell SR. 2011. Human natural killer cells proliferate and die in vivo more rapidly than T cells in healthy young and elderly adults. J. Immunol. 186:4590. {PubMed ID 21402893}
Cichocki F, Felices M, McCullar V, Presnell SR, Al-Attar A, Lutz CT, and Miller JF. 2011. Cutting Edge: MicroRNA-181 promotes human NK cell development by regulating Notch signaling. J Immunol 187: 6171. {PubMed ID 22084432}
Presnell SR, Zhang L, Chlebowy CN, Al-Attar A, and Lutz CT. 2012. Differential transcription factor use by the KIR2DL4 promoter under constitutive and IL-2/IL-15-treated conditions. J Immunol 188: 4394. {PubMed ID 22467658}
Lutz, CT and Quinn, LS. 2012. Sarcopenia, obesity, and natural killer cell immune senescence in aging: altered cytokine levels as a common mechanism. Aging 4: 535. {PubMed ID 22935594}
Segerstrom SC, Al-Attar A, Lutz CT. 2012. Psychosocial resources, aging, and natural killer cell terminal maturity, Psychology and Aging In Press. {PubMed ID 22708535}
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