Killer immunoglobulin-like receptor transcriptional regulation: A fascinating dance of multiple promoters

Killer immunoglobulin-like receptors (KIRs) recognize class I major histocompatibility complex molecules and participate in the calibration of activation thresholds during human natural killer (NK) cell development. The stochastic expression pattern of the KIR repertoire follows the product rule, meaning that the probability of the coexpression of two or more different KIRs equals the product of the individual expression frequencies for those KIRs. The expression frequencies of individual KIRs are independent of major histocompatibility complex class I and are instead established and maintained by a dynamic, yet ill-defined, transcriptional program. Here, we review recent advances in our understanding of the architecture of the regulatory regions within KIR genes and discuss a potential role for non-coding RNA in KIR transcriptional regulation during NK cell development. Understanding the molecular mechanisms that underlie KIR expression may help guide us in the design of novel, rational strategies for the use of NK cells in transplantation and immunotherapy.