Structural and functional differences between the promoters of independently expressed killer cell Ig-like receptors

Killer Ig-like receptors (KIR) are important for the recognition and elimination of diseased cells by human NK cells. Myeloid leukemia patients given a hematopoietic stem cell transplantation, for example, benefit from KIR-mediated NK alloreactivity directed against the leukemia cells. To establish an effective NK cell repertoire, most KIR genes are expressed stochastically, independently of the others. However, the sequences upstream of the coding regions of these KIR genes are highly homologous to the recently identified KIR3DL1 promoter (91.1-99.6% sequence identity), suggesting that they are regulated by similar if not identical mechanisms of transcriptional activation. We investigated the effects of small sequence differences between the KIR3DL1 promoter and other KIR promoters on transcription factor binding and promoter activity. Surprisingly, electrophoretic mobility shift assays and promoter-reporter assays revealed significant structural and functional differences in the cis-acting elements of these highly homologous KIR promoters, suggesting a key role for transcription factors in independent control of expression of specific KIR loci. Thus, the KIR repertoire may be shaped by a combination of both gene-specific and stochastic mechanisms.