Killer-cell immunoglobulin-like receptor

Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. In humans, they are encoded in the leukocyte receptor complex (LRC) on chromosome 19q13.4; the KIR region is approximately 150 kilobases and contains 14 loci, including 7 protein-coding genes (some duplicated) and 2 pseudogenes.

They regulate the killing function of these cells by interacting with major histocompatibility (MHC) class I molecules, which are expressed on all nucleated cell types. KIR receptors can distinguish between MHC I allelic variants, which allows them to detect virally infected cells or transformed cells. KIRs are paired receptors, meaning some have activating and others have inhibitory functions; most KIRs are inhibitory: their recognition of MHC molecules suppresses the cytotoxic activity of their NK cell.

A limited number of KIRs are activating: their recognition of MHC molecules activates the cytotoxic activity of their cell. Initial expression of KIRs on NK cells is stochastic, but NK cells undergo an educational process as they mature that alters the KIR expression to maximize the balance between effective defense and self-tolerance. KIR's role in killing unhealthy self-cells and not killing healthy self-cells, involves them in protection against and propensity to viral infection, autoimmune disease, and cancer. KIR molecules are polymorphic: their gene sequences differ greatly across individuals. They are also polygenic so that it is rare for two unrelated individuals to possess the same KIR genotype.

Unlike T lymphocytes, resting NK cells use preformed lytic granules to kill target cells, implying a rapid cytolytic effect that requires a finely regulated control mechanism. The ability to spare normal tissues, but not transformed cells, is termed the "missing self" hypothesis. This phenomenon is determined by MHC class I–specific inhibitory receptors that functionally dominate the triggering potentials induced by activating receptors. Thus, NK cells use a complex array of inhibitory or activating receptor/ligand interactions, the balance of which regulates NK cell function and cytolytic activity. Receptors displaying this function evolved during phylogenesis following the rapid evolution of genes coding for MHC class I molecules. Thus, in primates and a few other species, evolved MHC class I–inhibitory receptors belong to the KIR immunoglobulin superfamily, while in rodents and other species the same function is under the control of type II integral transmembrane glycoproteins, structurally characterized as disulfide-linked homodimers belonging to the Ly49 protein family.