Killer-Cell Immunoglobulin-Like Receptors
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P221-223
2025-12-10
28
KIRs provide one method by which NK cells recognize self from non self in order to mediate an appropriate cytotoxic response. In total, 16 KIR genes have been identified on chromosome 19q13.4. Structurally, the KIR protein contains two or three extracellular immunoglobulin like domains that have the ability to recognize MHC class I proteins, namely HLA-A, HLA-B, and HLA-C. KIRs may be either inhibitory or activating, a functional feature that derives from the structure and enzymatic activity of the intracellular tyrosine-based motif of the KIR protein. An examination of KIR nomenclature provides information on the number of extracellular domains, the function of the intracellular motif, and the existence of polymorphic versions. The designation 2D or 3D indicates the number of immunoglobulin-like extracellular domains, while the length of the intracytoplasmic tail may be either long (L) and inhibitory, or short (S) and activating. A suffix numeral appearing at the very end of the KIR nomenclature indicates the existence of a polymorphic form of that particular receptor. For example, the terms KIR2DS2 and KIR2DS3 indicate the polymorphic forms of an activating KIR that displays two extra cellular domains. The KIRs have been designated as members of the CD158 series.
The KIR molecules provide NK cells with the ability to sense the absence of self-HLA molecules on potential target cells—a process which was originally referred to by K. Karre and early investigators as the detection of “missing self.” The 16 KIR genes are encoded by a family of homologous genes 10-16 kb in size that have been mapped to chromosome 19q13.4 where they are tightly arranged in a head-to tail fashion. There are 14 KIR genes and 2 KIR pseudogenes. There are eight inhibitory KIR (KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 3DL2, and 3DL3) and six activating KIR (KIR2DS1, 2DS2, 2DS3, 2DS4, 2DS5, and 3DS1). The pseudogenes are designated KIR2DP1 and KIR3DP1). The long tails of the inhibitory KIRs contain 1 or 2 copies of immunoreceptor tyrosine-based inhibition motifs (ITIMs) that undergo phosphorylation following interaction with specific HLA class I ligand and recruit Src homology region 2 domain containing phosphatase 1 and 2 (SHP-1, -2) that switch off the NK cell response. The short-tails of the activating KIRs lack ITIMs and instead are characterized by a positively charged amino acid residue in the transmembrane region that promotes the interaction with the 12 kDa DNAX activation protein (DAP-12). DAP12 contains immunoreceptor tyrosine-based activation motifs which initiate activating signals in response to ligand binding.
Since they are organized in the form of a tightly linked cluster, the KIR genes are inherited as haplotypes with an individual receiving maternal and paternal contributions. KIR3DL3, 3DP1, 2DL4, and 3DL2 are present in every haplotype and are referred to as “frame work” genes. KIR3DL3 is located at the 5′ centromeric end of the haplotype and KIR3DL2 is located at the 3′ telomeric end with KIR3DP1 and KIR2DL4 being located in the middle of the KIR gene complex separated by a 14 kb sequence that is enriched with L1 repeats. Thus, the centromeric half of the KIR haplotype is delimited by KIR3DL3 and 3DP1, and the telomeric half is delimited by KIR2DL4 and 3DL2. The KIR genes contained within these centromeric and telomeric regions enable the KIR haplotypes to be broadly classified into two categories, namely group A or group B. Group A haplotypes exhibit a fixed gene content that consists of KIR3DL3… 2DL3…2DP1…2DL1…3DP1…2DL4…3DL1…2DS4…3DL2 in that order, with the framework genes having been underlined. In contrast, group B haplotypes are variable both in the number and combinations of KIR genes and contain several KIR genes (2DL2, 2DL5, 2DS1, 2DS2, 2DS3, 2DS5, 3DS1) that are not part of the A haplotype. Group A haplotypes contain only one activating gene (KIR2DS4), but group B haplotypes may contain up to five different activating KIRs, namely KIR2DS1, 2DS2, 2DS3, 2DS5, and 3DS1.
KIRs recognize specific peptide motifs of HLA class I molecules which are the products of MHC genes located on chromosome 6. The human MHC encodes for six functional HLA class I genes. HLA-A, HLA-B, and HLA-C represent the so-called classical class I genes and are highly polymorphic. The genes for HLA-E, HLA-F, and HLA-G encode non-classical class I molecules that are conserved. All of these class I molecules interact with NK cell receptors with the receptors for HLA-F having only recently been identified (Fig. 1). The alleles of the HLA-C locus can be placed into two groups of ligands (C1 and C2) based on the amino acid present at position 80 of the protein. HLA-C group 1 with asparagine at position 80 provides the ligand for KIR2DL2 and KIR2DL3, whereas HLA-C group 2 with lysine at position 80 provides the ligand for KIR2DL1. The HLA-Bw4 epitope at residues 77–83 of the HLA-B α1 domain is recognized by KIR3DL1. HLA-A3/11 serves as the ligand for KIR3DL2. While the ligands for inhibitory KIR have become well-defined, the ligand specificity of the activating KIR remains a subject of investigation. Recent studies indicate that KIR2DL4 is able to mediate both inhibitory and activating functions. Also, in addition to recognition of HLA-C1, KIR2DL2/L3 can weakly recognize some HLA-C2 alleles and the HLA-B*4601 and HLA-B*7301 alleles that bear the HLA C1 epitope.
Fig1. SIMPLIFIED REPRESENTATION OF HUMAN KIR MOLECULES AND THEIR HLA LIGANDS. There are 16 human KIR genes, 8 inhibitory, 6 activating, and 2 pseudogenes (not shown). The known HLA ligands are presented as binding partners. The ligands for several of the stimulatory KIRs have not yet been confirmed. HLA, Human leukocyte anti gen; Ig, immunoglobulin; KIR, killer immunoglobulin-like receptor. (From Rajalingam R. Diversity of killer cell immunoglobulin-like receptors and disease. Clin Lab Med. 2018;38(4):637–653.)
Genotyping efforts reveal that all human populations possess group A and group B haplotypes, but their frequencies vary consider ably. People of European descent and African Americans commonly carry both A and B haplotypes, whereas the homozygous group-A KIR haplotype (AA genotype) is common in Northeast Asians (i.e., Japanese, Koreans, and Chinese). The AB or BB genotypes are common in the Indigenous populations of India, Australia, and America and the NK cells of these individuals may contain up to 6 activating KIRs. The prehistoric migrations of these populations may have provided environmental selective pressure in favor of haplotypes enriched in activating KIR.
Individual KIR genes exhibit a high level of allelic polymorphism that can affect protein expression, affinity for HLA molecules, strength of the inhibitory/activating signal, and downstream cytotoxicity and cytokine release. The inhibitory KIR exhibit greater sequence poly morphism than the activating KIRs. Generally, inhibitory receptors bind with greater avidity or attraction for a corresponding HLA anti gen than activating receptors. Thus, if an NK cell expresses both activating and inhibitory KIR for an identical ligand, the NK cell will generally be inhibited from killing. Combinations of HLA variant and KIR genes exert an influence of resistance to viral infections, susceptibility to some autoimmune diseases, several pregnancy syndromes as well as the outcome of bone marrow transplantation. Specific KIR/HLA allele pairings have been associated with improved outcomes in HIV and hepatitis C infection.
KIR2DL4 is present in all KIR haplotypes, and the presence of a positively charged arginine in its transmembrane region and a single ITIM moiety enables it to generate both a weak inhibitory signal as well as an activation program that leads to the secretion of pro inflammatory and proangiogenic cytokines. HLA-G is expressed almost exclusively in fetal trophoblast cells at the maternal-fetal interface and its soluble form is the only known ligand for KIR2DL4 which is localized to NK cell endosomes. Uptake of soluble HLA-G by NK cell endosomal KIR2DL4 leads to endosomal signaling and the secretion of a collection of factors that favors embryo implantation, placental development, and successful pregnancy.
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