The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published 20 January 2003. doi:10.1084/jem.20021127
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© Rockefeller University Press, 0022-1007/2003/1/245 $5.00
The Journal of Experimental Medicine, Volume 197, Number 2, 245-255

DNA Methylation Maintains Allele-specific KIR Gene Expression in Human Natural Killer Cells

Huei-Wei Chan1, Zoya B. Kurago1,2, C. Andrew Stewart4, Michael J. Wilson4, Maureen P. Martin5, Brian E. Mace1, Mary Carrington5, John Trowsdale4 and Charles T. Lutz1,3

1 Department of Pathology, Oral Radiology, and Oral Medicine
2 Department of Oral Pathology, Oral Radiology, and Oral Medicine
3 Graduate Programs in Immunology and Molecular Biology, University of Iowa, Iowa City, IA 52242
4 Immunology Division, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom
5 Basic Research Program, SAIC Frederick, National Cancer Institute, Frederick, MD 21702

Address correspondence to Charles T. Lutz, Department of Pathology, University of Iowa, Iowa City, IA 52242. Phone: 319-335-8151; Fax: 319-335-8916; E-mail: charles-lutz{at}uiowa.edu

Killer immunoglobulin-like receptors (KIR) bind self–major histocompatibility complex class I molecules, allowing natural killer (NK) cells to recognize aberrant cells that have down-regulated class I. NK cells express variable numbers and combinations of highly homologous clonally restricted KIR genes, but uniformly express KIR2DL4. We show that NK clones express both 2DL4 alleles and either one or both alleles of the clonally restricted KIR 3DL1 and 3DL2 genes. Despite allele-independent expression, 3DL1 alleles differed in the core promoter by only one or two nucleotides. Allele-specific 3DL1 gene expression correlated with promoter and 5' gene DNA hypomethylation in NK cells in vitro and in vivo. The DNA methylase inhibitor, 5-aza-2'-deoxycytidine, induced KIR DNA hypomethylation and heterogeneous expression of multiple KIR genes. Thus, NK cells use DNA methylation to maintain clonally restricted expression of highly homologous KIR genes and alleles.

Key Words: killer cells, natural • killer inhibitory receptor • alleles • DNA methylation • gene expression regulation


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