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

Author:

Chan Huei-Wei1,Kurago Zoya B.12,Stewart C. Andrew3,Wilson Michael J.3,Martin Maureen P.4,Mace Brian E.1,Carrington Mary4,Trowsdale John3,Lutz Charles T.15

Affiliation:

1. Department of Pathology, Oral Radiology, and Oral Medicine

2. Department of Oral Pathology, Oral Radiology, and Oral Medicine

3. Immunology Division, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom

4. Basic Research Program, SAIC Frederick, National Cancer Institute, Frederick, MD 21702

5. Graduate Programs in Immunology and Molecular Biology, University of Iowa, Iowa City, IA 52242

Abstract

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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