Microbiology, Immunology & Molecular Genetics

Office: (859) 323-0356 Fax: (859) 323-2094 Email: ctlutz2@uky.edu

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. CD16-CD56low NK cells. NK cells that express low-level CD56 but do not express CD16 are distinct from the more common mature CD56dim NK cell subset, but little is known about these NK cells. We found that, unlike CD56dim NK cells, few CD16-CD56low NK cells expressed KIR. We also demonstrated that these cells rapidly respond to tumor cells with cytotoxic granule exocytosis and IFN-g production. We will further characterize CD16-CD56low NK cells in human health and disease.

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.

The goals are to characterize how NK cells control expression of the killer immunoglobulin-like receptor (KIR) genes.  We will investigate how epigenetic drugs used to treat myelodysplastic syndrome and lymphoma modify KIR gene expression.  We also will investigate how microRNAs are regulated by NK cells and how they influence NK mRNA expression.

Selected Recent Publications:

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. {21402893}

Butler JE, Moore MB, Chan W-C, Presnell SR, Chalupny NJ and Lutz CT. 2009. Proteasome regulation of ULBP1 transcription. J. Immunol. 182: 6600. {19414815}

Presnell SR, Zhang L, Ramilo CA, Chan H-W, and Lutz CT. 2006. Functional redundancy of transcription factor binding sites in the killer cell immunoglobulin-like receptor (KIR) gene promoter.  Int. Immunol. 18:1221. {16818466}

Chan H-W, Miller JS, Moore MB, and Lutz CT. 2005. Epigenetic control of highly homologous killer Ig-like receptor gene alleles. J. Immunol. 175:5966. {16237090}

Lutz CT, Moore MB, Bradley S, Shelton BJ, and Lutgendorf SK. 2005. Reciprocal age related change in natural killer cell receptors for MHC class I. Mech. Ageing Dev., 126:722. {15797305}

Lutgendorf SK, Moore MB, Bradley S, Shelton BJ, and Lutz CT. 2005. Distress and expression of natural killer receptors on lymphocytes.  Brain Behav. Immun. 19:185. {15797305}

Chan W-C, Kurago ZB, Stewart A, Wilson MJ, Martin MP, Mace BE, Carrington M, Trowsdale J and Lutz CT.  2003. DNA methylation maintains allele-specific KIR gene expression in human NK cells. J Exp Med 197:245. {12538663}

Moore M, Kurago Z, Fullenkamp CA and Lutz CT. 2003. Squamous cell carcinoma cells differentially stimulate NK cell effector functions: the role of IL-18. Cancer Immunol Immunotherapy 52:107. {12594574}

Lutz, C.T. and Z.B. Kurago. 1999. HLA class I expression on squamous cell carcinoma cells regulates natural killer cell activity. Cancer Res 59:5793. {10582701}

Shi, Y., K.D. Smith, and C.T. Lutz. 1998. TAP-independent MHC class I peptide antigen presentation to alloreactive CTL is enhanced by target cell incubation at subphysiological temperature. J Immunol 160:1573. {9574533}

Kurago, Z. B., C. T. Lutz, K. D. Smith, and M. Colonna. 1998. NK cell natural cytotoxicity and IFN-g production are not always coordinately regulated:  Engagement of DX9 KIR+ NK cells by HLA-B7 variants and target cells. J Immunol 160:1573. {9469412}

Smith, K. D. and C. T. Lutz. 1997. Alloreactive T cell recognition of MHC class I molecules:  The T cell receptor interacts with limited regions of the MHC class I long a-helices. J Immunol 158:2805. {9058816}

Shi, Y., K. D. Smith, M. G. Kurilla, and C. T. Lutz. 1997. Cytotoxic CD8+ T cells recognize EBV antigen but poorly kill autologous EBV-infected B lymphoblasts:  Immunodominance is elicited by a peptide epitope that is presented at low levels in vitro. J Immunol 159:1844. {9257848}

Vigna, J. L., K. D. Smith, and C. T. Lutz. 1996. Invariant chain associates preferentially with HLA class I/b2-microglobulin heterodimers in an allele-specific manner, and association is influenced by peptide binding groove residues. J Immunol 157:4503. {8906828}

Smith, K. D., B. E. Mace, A. Valenzuela, J. L. Vigna, J. A. McCutcheon, J. A. Barbosa, E. Huczko, V. H. Engelhard, and C. T. Lutz. 1996. Probing HLA-B7 conformational shifts induced by peptide-binding groove mutations and bound peptide with anti-HLA monoclonal antibodies. J Immunol 157:2470. {8805647}