Killer cell immunoglobulin-like receptors (KIRs) are expressed in a clonally restricted manner by human natural killer (NK) cells and allow detection of aberrant cells with low major histocompatibility complex class I levels. Clonally restricted KIR transcription is maintained by demethylation of the proximal promoter. Antisense transcripts also arise from this promoter and may enforce silencing of nonexpressed methylated KIR alleles in NK cells. Here we show that interleukin (IL)-2 and IL-15, cytokines critical for NK cell development and maintenance, greatly stimulated KIR3DL1 reverse promoter activity, but not forward promoter activity. Activated STAT5 was both necessary and sufficient for this effect and bound to the promoter in NK cells that expressed KIR3DL1 or were poised for expression. A systematic investigation of the KIR3DL1 reverse promoter showed significant differences from the forward promoter, with STAT and YY1 sites having relatively greater roles in regulating reverse proximal promoter activity. On the basis of our data, we propose a new role for antisense transcripts in the initiation of KIR gene expression during NK cell development.
|Number of pages
|Genes and Immunity
|Published - Mar 2013
Bibliographical noteFunding Information:
We thank Koichi Ikuta, Peter Cockerill, and John Trowsdale for reagents, the National Cancer Institute for IL-2, and Steve Anderson, Frank Cichocki and Jeffrey Miller for helpful discussions. Ahmad Al-Attar expertly formatted the figures. This work was supported by National Institute of Health grant, R01 AI56506.
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