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 Activating and inhibitory KIR receptors are expressed on NK cells in patchy, variegated combinations, leading to distinct NK cells. KIR gene expression is regulated by mechanisms of DNA methylation. The HLA class I regulated control of NK cell function can be exploited in an allogeneic bone marrow transplantation setting to eradicate acute myeloid leukemias
.The IgSF and CTLR superfamily inhibitory receptors expressed on the surface of NK cells are each expressed on a subset of NK cells in such a way that not all classes of inhibitory NK cell receptors are expressed on each NK cell, but there is some overlap. This creates unique repertories of NK cells, increasing the
specificity with which NK cells recognize virally-infected and transformed self-cells. Expression of KIR receptors is determined primarily by genetic factors, but recent studies have found that
epigenetic mechanisms also play a role in KIR receptor expression. Activating and inhibitory KIR receptors that recognize the same class I MHC molecule are mostly not expressed by the same NK cell. This pattern of expression is beneficial in that target cells that lack inhibitory MHC molecules but express activating MHC molecules are extremely sensitive to cytolysis. Although initial expression of inhibitory and activating receptors on NK cells appears to be stochastic, there is an education process based on MHC class I alleles expressed by the host that determines the final repertoire of NK receptor expression. This process of education is not well understood. Different receptor genes are expressed primarily independently of other receptor genes, which substantiates the idea that initial expression of receptors is stochastic. Receptors are not expressed entirely independently of each other, however, which supports the idea that there is an education process that reduces the amount of randomness associated with receptor expression. Further, once an NK receptor gene is activated in a cell, its expression is maintained for many cell generations. It appears that some proportion of NK cells are developmentally immature and therefore lack inhibitory receptors, making them hyporesponsive to target cells. In the human fetal liver, KIR and CD49 receptors are already expressed by NK cells, indicating that at least some KIR receptors are present in fetal NK cells, although more studies are needed to substantiate this idea. Although the induction of NK receptor expression is not fully understood, one study found that human
progenitor cells cultured
in vitro with
cytokines developed into NK cells, and many of these cells expressed CD94/NKG2A receptors, a CTLR receptor. Moreover, there was little to no KIR receptor expression in these cells, so additional signals are clearly required for KIR induction. The balance between effective defense and
self-tolerance is important to the functioning of NK cells. It is thought that NK cell self-tolerance is regulated by the educational process of receptor expression described above, although the exact mechanism is not known. The “at least one” hypothesis is an attractive, though not yet fully substantiated, hypothesis that tries to explain the way in which self-tolerance is regulated in the education process. This hypothesis posits that the NK cell repertoire is regulated so that at least one inhibitory receptor (either of the IgSF or CTLR superfamily) is present on every NK cell, which would ensure self-tolerance. Effective defense requires an opposing pattern of receptor expression. The co-expression of many MHC-specific receptors by NK cells is disfavored, likely because cells that co-express receptors are less able to attack virally infected or transformed cells that have down-regulated or lost one MHC molecule compared to NK cells that co-express receptors to a lesser degree. Minimization of co-expression, therefore, is important for mounting an effective defense by maximizing the sensitivity of response. == Evolution of KIRs across species ==