Killer-cell immunoglobulin-like receptor

[1][2] 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.

[6] 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.

The ability to spare normal tissues, but not transformed cells, is termed the "missing self" hypothesis.

[11][13][14][15][16][17] 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,[18][19][20] 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.

[12][23] 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)).

[20] 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.

[20][23] 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).

[23] 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).

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.

[23] 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.

[23] Activating and inhibitory KIR receptors that recognize the same class I MHC molecule are mostly not expressed by the same NK cell.

[23] 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.

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.

[23] Minimization of co-expression, therefore, is important for mounting an effective defense by maximizing the sensitivity of response.

[23] The KIR gene cluster has approximately 150 kb and is located in the leukocyte receptor complex (LRC) on human chromosome 19q13.4.

[6] This indicates that stronger selection is occurring on the 5′ exons, which encodes the extracellular part of the KIR that binds to the MHC.

[6] There is, therefore, evidence of strong selection on the KIR ligand binding sites, which is consistent with the high specificity of the KIR ligand binding site, as well as the rapid evolution of class I MHC molecules and viruses.

Inheritance of maternal and paternal haplotypes results in further diversity of individual KIR genotype.

[23] As a result of the huge migrations peoples indigenous to India, Australia, and the Americas made from Africa, activating KIR receptors became advantageous to these populations, and as a result these populations acquired activating KIR receptors.

Genotypes that are inhibitory KIR receptor dominant are likely susceptible to infection and reproductive disorders but protective against autoimmune diseases, whereas activating KIR receptor dominant genotypes are likely susceptible to autoimmunity but protective against viral infection and cancer.

[26][27] The Killer-cell immunoglobulin-like receptors (KIR) are being explored[28][29][30] as an alternative activation method in CAR T cell therapy.

Research is ongoing[31][32] to determine the effectiveness and safety of using KIR-based activation in CAR T cell treatments.