IL-2/IL-15 activate the human clonally-restricted KIR3DL1 reverse promoter

Killer cell immunoglobulin-like receptors (KIR) are expressed in a clonally-restricted fashion by human natural killer (NK) cells and allow detection of aberrant cells with low MHC 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 alleles in NK cells. Here we show that 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 playing relatively greater roles in regulating reverse proximal promoter activity. Based on our data, we propose a new role for antisense transcripts in the initiation of KIR gene expression during NK cell development.