Receptor Gene Cluster: Tuning the Genome for Defense ∗

Killer immunoglobulin-like receptors (KIRs) are molecules ex- pressed on the surface of natural killer (NK) cells, which play an important role in innate immunity. KIR recognition of major histo- compatability complex (MHC) class I allotypes represents one com- ponent of the complex interactions between NK cells and their tar- gets in determining NK cell reactivity. KIRs are encoded by a gene cluster at human chromosome 19q13.4. Despite their high degree of sequence identity, KIR genes encode proteins that have diverse recognition patterns (specific HLA class I allotypes) and confer op- posing signals (activating or inhibitory) to the NK cell. The KIR gene cluster is highly polymorphic, with individual genes exhibiting allelic variability and individual haplotypes differing in gene content. The polymorphism of the KIR locus parallels that of the MHC, facilitat- ing the adaptation of the immune system to a dynamic, challenging environment. This variation is associated with a growing number of human diseases, which is likely to extend to levels observed for the HLA loci. Here we review current progress in understanding KIR biology and genetics.