Disease relevance of KIR2DL1

• Because of the known association of human leucocyte antigen (HLA)-Cw*06 with psoriasis, the study concentrated on the five KIR genes that have HLA-C as their recognized ligand (i.e., KIR2DL1, -2DL2, -2DL3, -2DS1, and -2DS2) [1].
• Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis [2].
• CONCLUSION: This report is the first to describe the presence of autoantibodies to KIR2DL (p58.1 and p58.2) in the sera of patients with systemic autoimmune diseases [3].
• In the patient with brain death due to HSV infection, serial measurements of the CK BB activity in the CSF have shown a maximal fourfold increase from the value of 45 nkat/liter found on admission [4].
• Patients with septicemia, pancreatitis, acute respiratory distress syndrome, or other severe diseases had PLA2 values up to 540 U/L (9000 nkat/L) [5].

High impact information on KIR2DL1

• We report here the crystal structure of the inhibitory human killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) bound to its class I MHC ligand, HLA-Cw4 [6].
• Specifically, we use fluorescence lifetime imaging (FLIM) to report Förster resonance energy transfer (FRET) between GFP-tagged KIR2DL1 and a Cy3-tagged generic anti-phosphotyrosine monoclonal antibody [7].
• KIR2DS1 and its inhibitory homologue, KIR2DL1, share sensitivity to peptide sequence alterations at positions 7 and 8 [8].
• However, parallel examination of NK cell membrane lipid rafts revealed that KIR2DL1 signaling is critical for blocking lipid raft polarization and NK cell cytotoxicity [9].
• The latter were generated by truncating the KIR2DL1 cytoplasmic tail or by introducing mutations in the immunoreceptor tyrosine-based inhibition motifs [9].

Biological context of KIR2DL1

• The crystal structure of the inhibitory receptor, KIR2DL1, revealed a relationship to the hematopoietic receptor family, suggesting that the signaling mechanism of KIR2D molecules may resemble that of the hematopoietic receptors, and involve KIR2D dimerization [10].
• We provide a detailed analysis of their haplotypes and identify new alleles for KIR3DL3 and KIR2DL1 [11].
• Thus, the deletion of the N-linked glycosylation signal in HLA-Cw4 and -Cw6 greatly reduced recognition by KIR2DL1 [12].
• We hypothesized that either activatory KIR2DS1 or inhibitory KIR2DL1 gene frequencies might be different in psoriatic patients from a control population [13].
• Therefore, receptor-ligand clustering at the inhibitory NK immune synapse occurs independently of KIR2DL1 signal transduction [9].

Anatomical context of KIR2DL1

• In 5 (7%) of the 68 individuals in whom the KIR2DL1 gene was present and in 10 (15%) of the 67 in whom KIR3DL1 was present, the corresponding receptor was not expressed by NK cells, as determined by flow cytometry analysis [14].
• This molecule is recognized by the inhibitory receptor KIR2DL1 and the activatory receptor KIR2DS1, which are expressed on natural killer cells and subpopulations of T lymphocytes [13].
• RESULT(S): The percentage of cells that expressed KIR2DL1 among NK (KIR2DL1(+)NK) cells in peritoneal fluid and peripheral blood was significantly higher in women with endometriosis than in controls [2].
• Homozygosity for human leucocyte antigen-C ligands of KIR2DL1 is associated with increased risk of relapse after human leucocyte antigen-C-matched unrelated donor haematopoietic stem cell transplantation [15].
• However, the expression of p58.1 by NK TILs and by CD3(+)CD56(+) TILs in patients with HCC was significantly decreased compared to that of hepatic lymphocytes of the control subjects (8.9% vs 37.85%, P = 0.047; 4.1% vs 25.2%, P = 0.049, respectively) [16].

Associations of KIR2DL1 with chemical compounds

• The overall fold of this structure, like KIR2DL1, exhibits K-type Ig topology with cis-proline residues in both domains that define beta-strand switching, which sets KIR apart from the C2-type hematopoietic growth hormone receptor fold [17].
• One soluble KIR2D, derived from an inhibitory receptor with a long cytoplasmic tail (KIR2DL1), bound to HLA-C allotypes containing asparagine 77 and lysine 80 in the heavy chain, as expected, since these allotypes inhibit lysis by NK cells expressing KIR2DL1 [18].
• We have engineered a disulfide-linked dimer of KIR2DL1 by introducing a free cysteine at the C-terminal stem region of the receptor [10].
• Replacement of the amino-terminal His residue by Ala abolishes the ability of KIR2DL1 to bind Co(2+), indicating that Co(2+)-mediated KIR2DL1 dimerization involves pairing of the D1 domain [19].
• Although not observed on native gels, the inhibitory receptor KIR2DL1 can be chemically cross-linked into dimers in the presence of Zn(2+) and its related divalent metal ions, suggesting that Co(2+)-mediated dimerization of KIR2DL1 may mimic a weaker interaction between KIR2DL1 and zinc in vivo [19].

Physical interactions of KIR2DL1

• Our present data indicate that a single amino acid difference greatly influences the p58.1/p50.1 affinity for their HLA-C ligand and suggests a possible role of position 70 as a contact site in the natural killer cell receptor/major histocompatibility complex class I interaction [20].

Other interactions of KIR2DL1

• Here we use surface plasmon resonance to study the binding of soluble forms of KIR2DL1 and KIR2DL3 to several peptide-HLA-Cw7 complexes [21].
• The hinge angle of KIR2DL2 is approximately 80 degrees, 14 degrees larger than that observed in KIR2DL1 despite the existence of conserved hydrophobic residues near the hinge region [17].
• The binding of KIR2DS4-Ig to HLA-Cw4 is weaker than that of killer cell Ig-like receptor two-domain long tail number 1 (KIR2DL1)-Ig fusion protein; however, such weak recognition is capable of inhibiting lysis by an NK transfectant expressing a chimeric molecule of KIR2DS4 fused to the transmembrane and cytoplasmic portion of KIR2DL1 [22].
• The possible role of carbohydrate in the interaction of HLA-C with a human inhibitory natural Killer cell Immunoglobulin-like Receptor with two Ig domains, KIR2DL1, was investigated [12].
• The differences are due to typing of KIRs KIR2DL1 and KIR2DS5, and may be explained by technical differences or the inability to type new variants [23].

Analytical, diagnostic and therapeutic context of KIR2DL1

• A single amino acid mutation at position 70, obtained by site-directed mutagenesis, was found to affect the binding affinity of both the p50.1 and the p58.1 receptors [20].
• Patients who had tracheostomy performed for tracheobronchial toilet had a significantly shorter cannulation time than those with the other two indications (log-rank test, chi2(2) = 47.11; p < .00001) [24].

References