Regulation of class I major histocompatibility complex receptor expression in natural killer cells: one promoter is not enough!

Summary:  The class I major histocompatibility complex (MHC) receptors expressed by natural killer (NK) cells play an important role in regulating their function. The number and type of inhibitory receptors expressed by NK cells must be tightly controlled in order to avoid the generation of dominantly inhibited NK cells. The selective stochastic expression of the class I MHC receptors generates a variegated NK cell population capable of discriminating subtle changes in MHC expression on potential target cells. The molecular mechanisms controlling the cell‐specific and probabilistic expression of these receptors are without doubt very complex. The traditional approach of considering a core promoter modulated by upstream enhancer elements is likely too simplistic a paradigm to adequately explain the regulation of these genes, as well as other gene clusters that are not expressed in an ‘all or none’ fashion. Our studies on the regulation of the mouse Ly49 and human killer immunoglobulin‐like receptor (KIR) clusters of class I MHC receptor genes have revealed the presence of multiple transcripts in both sense and antisense orientations. In both systems, an antisense promoter overlaps a promoter that produces sense transcripts, creating a bidirectional element. In the Ly49 genes, the competing promoters behave as probabilistic switches, and it is likely that the human bidirectional promoters will have a similar property. The antisense transcripts generated in the Ly49 genes are far removed from the promoter responsible for Ly49 expression in mature NK cells, whereas the antisense KIR transcripts detected are within the adult promoter region. This finding suggests that the mechanism of promoter regulation in the KIR genes may be quite different from that of the Ly49 genes. This review summarizes the current state of knowledge regarding class I MHC receptor gene regulation. The models proposed for the control of the probabilistic expression of the Ly49 and KIR genes are discussed in the context of current knowledge regarding the complex control of other well‐studied gene clusters such as the β‐globin and cytokine clusters.