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 seven protein-coding genes (some duplicated) and two pseudogenes. NK cells in humans use the KIRs to the perturbations from self-HLA class I molecules present on infected or HLA-disparate fetal transplants. The KIR receptors were originally defined serologically by the Moretta groups in the early 1990s. 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. The receptors collaborate to monitor and respond to the changes in HLA class I antigen on cells of the body. 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 infections such as HIV, HCV, 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. The factors controlling and regulating KIR expression on NK cells are not well understood. It is accepted that tolerance is a major driving force. Tolerance is a fundamental feature of the immune system and is required to prevent a system designed for attack from damaging itself.
Function
Role in natural killer cells Natural killer (NK) cells are a type of lymphocyte cell involved in the innate immune system's response to viral infection and tumor transformation of host cells. Like T cells, NK cells have many qualities characteristic of the adaptive immune system, including the production of “memory” cells that persist following encounter with antigens and the ability to create a secondary recall response. Unlike T cells, NK cell receptors are germline encoded, and therefore do not require somatic gene rearrangements. Because NK cells target self cells, they have an intricate mechanism by which they differentiate self and non-self cells in order to minimize the destruction of healthy cells and maximize the destruction of unhealthy cells. Natural killer cell cytolysis of target cells and cytokine production is controlled by a balance of inhibitory and activating signals, which are facilitated by NK cell receptors. NK cell inhibitory receptors are part of either the immunoglobulin-like (IgSF) superfamily or the C-type lectin-like receptor (CTLR) superfamily. Members of the IgSF family include the human killer cell immunoglobulin-like receptor (KIR) and the Immunoglobulin-like transcripts (ILT). CTLR inhibitory receptors include the CD94/NKG2A and the murine Ly49, which is probably analogous to the human KIR.
Role in T cells KIR and CD94 (CTLR) receptors are expressed by 5% of peripheral blood T cells. Killer immunoglobulin-like receptors on T cells have the function of signaling T cell activation. The KIRs are expressed on CD8+ T cells and will interact with the human leukocyte antigen (HLA) class I molecules on cells. The KIRs can signal the inhibitory or activate the signaling of the T cell and its ability to kill the foreign cells.
Nomenclature and classification
KIR receptors are named based on the number of their extracellular Ig-like domains (2D or 3D) and by the length of their cytoplasmic tail (long (L), short (S), or pseudogene (P)). The number following the L, S, or P in the case of a pseudogene, differentiates KIR receptors with the same number of extracellular domains and length of cytoplasmic tail. Finally, the asterisk after this nomenclature indicates allelic variants. Single substitutions, insertions, or deletions in the genetic material that encodes KIR receptors changes the site of termination for the gene, causing the cytoplasmic tail to be long or short, depending on the site of the stop codon. These single nucleotide alterations in the nucleotide sequence fundamentally alter KIR function. With the exception of KIR2DL4, which has both activating and inhibitory capabilities, KIR receptors with long cytoplasmic tails are inhibitory and those with short tails are activating.
Receptor types
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