Charles T. Lutz, M.D., Ph.D.
Professor
Doctoral Studies: University of Chicago.
Postdoctoral: Washington University, St. Louis.
Research Statement:
Natural killer (NK) lymphocytes bridge the innate and adaptive immune systems. NK cells recognize aberrant cells early in infection and tumor surveillance. NK cells kill aberrant cells and secrete cytokines to orchestrate subsequent adaptive immune responses. Unlike T and B lymphocytes, relatively little is known about how NK cells recognize “nonself.”
1. NK cell recognition of squamous cell carcinoma (SCC) cells. SCCs are the major cancers of the mouth and upper aerodigestive tract and are important cancers in many other organs. Little is know about how NK cells recognize epithelial cancers. We have shown that SCC cells stimulate NK cells via surface molecules and soluble interleukin 18. SCCs express MICA, MICB, ULBP2 and ULBP3, which stimulate both NK cells and T cells via their NKG2D receptors. Curiously, SCCs do not express two of the other known NKG2D ligands, ULBP1 and ULBP4. The cancer drug, bortezomib, and other proteasome inhibitors dramatically and specifically upregulate ULBP1 transcription and cell surface expression. We have mapped bortezomib-responsive elements to the ULBP1 promoter. Our goal is to discover how ULBP1 expression is regulated in cancer cells and to investigate how this affects immune recognition of solid tumors.
2. 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. Because CD94/NKG2A and most KIR are inhibitory receptors, they protect normal MHC class I-high cells from NK attack. KIR genes are expressed in a random fashion by NK cells. We showed that KIR gene expression is also allele-specific; individual NK cells may express either maternal, paternal, both, or neither allele of any particular KIR gene. We also showed that allele-specific KIR expression is controlled by promoter DNA methylation. We have recently discovered that individual KIR differ in their basal promoters, which in turn control the effectiveness of transcription factor binding elements in the enhanceosome. We will investigate the interplay between transcription factors and epigenetic control of KIR expression in normal NK cell development and in myelodysplastic syndrome and lymphoma patients treated with DNA methylation inhibitors.
3. Effects of aging on NK cell function. Immune function declines with normal aging in humans and laboratory animals. We found that fewer NK cells from elderly people express CD94/NKG2A than do NK cells from young adults. Our recent unpublished studies show that this is due to a lower proportion of immature NK cells. Our novel unpublished turnover studies show that elderly people produce fewer new NK cells than do young adults. We will characterize whether this is due to less NK cell production, an accumulation of senescent post-mitotic NK cells, or to faster NK maturation in the elderly.
Selected Recent Publications:
Butler, J.E., Moore, M.B., Presnell, S.R., Chan, H.-W., Chalupny, N.J., and Lutz, C.T. (2009). Proteasome regulation of ULBP1 transcription. J Immunol 162: 6600-09.
Presnell, S.R., Zhang, L., Ramilo, C.A., Chan, H.-W., and Lutz, C.T. (2006). Functional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter. Int Immunol 18, 1221-1232.
Lutz, C.T., Moore, M.B., Bradley, S., Shelton, B.J., and Lutgendorf, S.K. (2005). Reciprocal age related changes in natural killer receptors for MHC class I. Mech Ageing Dev 126, 722-731.
Chan, H.W., Miller, J.S., Moore, M.B., and Lutz, C.T. (2005). Epigenetic control of highly homologous killer Ig-like receptor gene alleles. J Immunol 175, 5966-5974.
Moore, M.B., Kurago, Z.B., Fullenkamp, C.F., and Lutz, C.T. (2003). Squamous cell carcinoma cells differentially stimulate NK cell effector functions: the role of IL-18. Cancer Immunology Immunotherapy 52, 107-115.
Chan, H.-W., Kurago, Z.B., Stewart, C.A., Wilson, M.J., Martin, M.P., Mace, B.E., Carrington, M., Trowsdale, J., and Lutz, C.T. (2003). DNA methylation maintains allele-specific KIR gene expression in human natural killer cells. J Exp Med 197, 245-255.
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