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
Inhibitory receptors Inhibitory receptors recognize self-MHC class I molecules on target self cells, causing the activation of signaling pathways that stop the cytolytic function of NK cells. Self-MHC class I molecules are always expressed under normal circumstance. According to the missing-self hypothesis, inhibitory KIR receptors recognize the downregulation of MHC class I molecules in virally-infected or transformed self cells, leading these receptors to stop sending the inhibition signal, which then leads to the lysis of these unhealthy cells. Because natural killer cells target virally infected host cells and tumor cells, inhibitory KIR receptors are important in facilitating self-tolerance.
KIR inhibitory receptors signal through their immunoreceptor tyrosine-based inhibitory motif (ITIM) in their cytoplasmic domain. When inhibitory KIR receptors bind to a ligand, their ITIMs are tyrosine phosphorylated and protein tyrosine phosphatases, including SHP-1, are recruited. Killer-cell immunoglobulin-like receptors initiate intracellular signaling pathways through NK cell behavior. The ITIMs are phosphorylated by the Src family kinases such as Lck and Fyn. The phosphatases dephosphorylate signals intermediates which blocks the activation and suppresses the cytotoxicity. It allows the natural killer cells to be deactivated when being in the presence of the healthy cells that are expressed in MHC class I levels. Activating KIRs will rely on the DAP12 which is an adaptor molecule that will contain immunoreceptor tyrosine-based activation motifs (ITAMs). KIRs contain a positively charged lysine in the transmembrane which can form a salt bridge with the negatively charged DAP12's acid and the ligand can signal to the tyrosine kinases such as SYK and ZAP-70 to create more activation signals. The activation signals would then lead to degranulation, cytokine production and the destruction of the target cells. The NK cell will only make a response depending how the inhibitory and activating signals work out, but the inhibitory signals have an overpower over the activating signals which will result in defense against cytotoxicity. Inhibition occurs early in the activation signaling pathway, likely through the interference of the pathway by these phosphatases.
Activating receptors Activating receptors recognize ligands that indicate host cell aberration, including induced-self antigens (which are markers of infected self cells and include MICA, MICB, and ULBP, all of which are related to MHC class 1 molecules), altered-self antigens (MHC class I antigens laden with foreign peptide), and/or non-self (pathogen encoded molecules). The binding of activating KIR receptors to these molecules causes the activation of signaling pathways that cause NK cells to lyse virally infected or transformed cells.
Activating receptors do not have the immunoreceptor tyrosine-base inhibition motif (ITIM) characteristic of inhibitory receptors, and instead contain a positively charged lysine or arginine residue in their transmembrane domain (with the exception of KIR2L4) that helps to bind DAP12, an adaptor molecule containing a negatively charged residue as well as immunoreceptor tyrosine-based activation motifs (ITAM). Activating KIR receptors include KIR2DS, and KIR3DS.
Much less is known about activating receptors compared to inhibitory receptors. A significant proportion of the human population lacks activating KIR receptors on the surface of their NK cells as a result of truncated variants of KIR2DS4 and 2DL4, which are not expressed on the cell surface, in individuals who are heterozygous for the KIR group A haplotype. This suggests that a lack of activating KIR receptors is not incredibly detrimental, likely because there are other families of activating NK cell surface receptors that bind MHC class I molecules that are probably expressed in individuals with this phenotype. Because little is known about the function of activating KIR receptors, however, it is possible that there is an important function of activating KIR receptors of which we are not yet aware.
Activating receptors have lower affinity for their ligands than do inhibitory receptors. Although the purpose of this difference in affinity is unknown, it is possible that the cytolysis of target cells occurs preferentially under conditions in which the expression of stimulating MHC class I molecules on target cells is high, which may occur during viral infection. This difference, which is also present in Ly49, the murine homolog to KIR, tips the balance towards self-tolerance.
Expression