Characterization of KIR intermediate promoters reveals four promoter types associated with distinct expression patterns of KIR subtypes

The human KIR genes contain multiple promoters that control the process of gene activation and variegated expression of KIR on NK and T cells. Specific subfamilies of KIR genes have differences in the timing and tissue-specificity of expression: however, previous studies of the proximal KIR promoters have not shown significant differences in activity between differentially expressed KIR gene subsets. The recent identification of an intermediate KIR promoter (ProI) associated with KIR2DL1 expression suggested a central role for this element in KIR expression. The current study identifies ProI elements in all of the KIR genes, revealing four classes of ProI that correspond with four distinct expression phenotypes of KIR sub-groups: KIR2DL2/S2/L3 that are expressed early in reconstituting NK after transplant; KIR2DL4 that is expressed by CD56-bright NK in a non-variegated manner; KIR3DL3 that is not expressed by circulating NK cells; and the remaining KIR that are expressed by subsets of CD56-dim NK. The four classes of ProI are structurally diverse and display distinct functional properties. Altogether, these results indicate that KIR ProI elements contribute to the tissue/cell type specificity of KIR transcription, and cooperate with the probabilistic proximal promoter to control KIR expression.