DNA methylation maintains allele-specific KIR gene expression in human natural killer cells.
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.
Chan
Huei-Wei
HW
Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
Kurago
Zoya B
ZB
Stewart
C Andrew
CA
Wilson
Michael J
MJ
Martin
Maureen P
MP
Mace
Brian E
BE
Carrington
Mary
M
Trowsdale
John
J
Lutz
Charles T
CT
D000483:Alleles; D002460:Cell Line; D002999:Clone Cells; D019175:DNA Methylation; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics*; D054340:Receptors, KIR; D054345:Receptors, KIR2DL4; D054341:Receptors, KIR3DL1; D054347:Receptors, KIR3DL2
D015395:Histocompatibility Antigens Class I; C515079:KIR2DL4 protein, human; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054345:Receptors, KIR2DL4; D054341:Receptors, KIR3DL1; D054347:Receptors, KIR3DL2