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Gene Review

KIR2DL1  -  killer cell immunoglobulin-like receptor,...

Homo sapiens

Synonyms: 47.11, CD158 antigen-like family member A, CD158A, KIR-K64, KIR221, ...
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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


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


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].


  1. Activating killer cell immunoglobulin-like receptor gene KIR2DS1 is associated with psoriatic arthritis. Williams, F., Meenagh, A., Sleator, C., Cook, D., Fernandez-Vina, M., Bowcock, A.M., Middleton, D. Hum. Immunol. (2005) [Pubmed]
  2. Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis. Maeda, N., Izumiya, C., Yamamoto, Y., Oguri, H., Kusume, T., Fukaya, T. Fertil. Steril. (2002) [Pubmed]
  3. Detection of autoantibodies to killer immunoglobulin-like receptors using recombinant fusion proteins for two killer immunoglobulin-like receptors in patients with systemic autoimmune diseases. Matsui, T., Otsuka, M., Maenaka, K., Furukawa, H., Yabe, T., Yamamoto, K., Nishioka, K., Kato, T. Arthritis Rheum. (2001) [Pubmed]
  4. Creatine kinase isoenzyme BB in cerebrospinal fluid from patients with meningitis and encephalitis. Briem, H., Lindquist, L., Lundbergh, P., Sego, E., Sköldenberg, B. J. Infect. Dis. (1983) [Pubmed]
  5. Characteristics and clinical application of a radiometric Escherichia coli-based phospholipase A2 assay modified for serum analysis. Aufenanger, J., Zimmer, W., Kattermann, R. Clin. Chem. (1993) [Pubmed]
  6. Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex. Fan, Q.R., Long, E.O., Wiley, D.C. Nat. Immunol. (2001) [Pubmed]
  7. Microclusters of inhibitory killer immunoglobulin-like receptor signaling at natural killer cell immunological synapses. Treanor, B., Lanigan, P.M., Kumar, S., Dunsby, C., Munro, I., Auksorius, E., Culley, F.J., Purbhoo, M.A., Phillips, D., Neil, M.A., Burshtyn, D.N., French, P.M., Davis, D.M. J. Cell Biol. (2006) [Pubmed]
  8. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. Stewart, C.A., Laugier-Anfossi, F., Vély, F., Saulquin, X., Riedmuller, J., Tisserant, A., Gauthier, L., Romagné, F., Ferracci, G., Arosa, F.A., Moretta, A., Sun, P.D., Ugolini, S., Vivier, E. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. Signaling at the inhibitory natural killer cell immune synapse regulates lipid raft polarization but not class I MHC clustering. Fassett, M.S., Davis, D.M., Valter, M.M., Cohen, G.B., Strominger, J.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  10. A disulfide-linked natural killer cell receptor dimer has higher affinity for HLA-C than wild-type monomer. Fan, Q.R., Long, E.O., Wiley, D.C. Eur. J. Immunol. (2000) [Pubmed]
  11. Detailed gene and allele content analysis of three homozygous KIR haplotypes. Murdoch, S., Seoud, M., Kircheisen, R., Mazhar, B., Slim, R. Tissue Antigens (2006) [Pubmed]
  12. N-linked carbohydrate on human leukocyte antigen-C and recognition by natural killer cell inhibitory receptors. Baba, E., Erskine, R., Boyson, J.E., Cohen, G.B., Davis, D.M., Malik, P., Mandelboim, O., Reyburn, H.T., Strominger, J.L. Hum. Immunol. (2000) [Pubmed]
  13. Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris. Łuszczek, W., Mańczak, M., Cisło, M., Nockowski, P., Wiśniewski, A., Jasek, M., Kuśnierczyk, P. Hum. Immunol. (2004) [Pubmed]
  14. Comparison of killer Ig-like receptor genotyping and phenotyping for selection of allogeneic blood stem cell donors. Leung, W., Iyengar, R., Triplett, B., Turner, V., Behm, F.G., Holladay, M.S., Houston, J., Handgretinger, R. J. Immunol. (2005) [Pubmed]
  15. 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. Giebel, S., Locatelli, F., Wojnar, J., Velardi, A., Mina, T., Giorgiani, G., Krawczyk-Kulis, M., Markiewicz, M., Wylezol, I., Holowiecki, J. Br. J. Haematol. (2005) [Pubmed]
  16. Expression of inhibitory receptors in natural killer (CD3(-)CD56(+)) cells and CD3(+)CD56(+) cells in the peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Yuen, M.F., Norris, S. Clin. Immunol. (2001) [Pubmed]
  17. Crystal structure of the HLA-Cw3 allotype-specific killer cell inhibitory receptor KIR2DL2. Snyder, G.A., Brooks, A.G., Sun, P.D. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  18. Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. Winter, C.C., Gumperz, J.E., Parham, P., Long, E.O., Wagtmann, N. J. Immunol. (1998) [Pubmed]
  19. Cobalt-mediated dimerization of the human natural killer cell inhibitory receptor. Fan, Q.R., Long, E.O., Wiley, D.C. J. Biol. Chem. (2000) [Pubmed]
  20. Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for HLA-Cw4 molecules. Biassoni, R., Pessino, A., Malaspina, A., Cantoni, C., Bottino, C., Sivori, S., Moretta, L., Moretta, A. Eur. J. Immunol. (1997) [Pubmed]
  21. Killer cell immunoglobulin receptors and T cell receptors bind peptide-major histocompatibility complex class I with distinct thermodynamic and kinetic properties. Maenaka, K., Juji, T., Nakayama, T., Wyer, J.R., Gao, G.F., Maenaka, T., Zaccai, N.R., Kikuchi, A., Yabe, T., Tokunaga, K., Tadokoro, K., Stuart, D.I., Jones, E.Y., van der Merwe, P.A. J. Biol. Chem. (1999) [Pubmed]
  22. Recognition of HLA-Cw4 but not HLA-Cw6 by the NK cell receptor killer cell Ig-like receptor two-domain short tail number 4. Katz, G., Markel, G., Mizrahi, S., Arnon, T.I., Mandelboim, O. J. Immunol. (2001) [Pubmed]
  23. A multi-laboratory characterization of the KIR genotypes of 10th International Histocompatibility Workshop cell lines. Cook, M.A., Norman, P.J., Curran, M.D., Maxwell, L.D., Briggs, D.C., Middleton, D., Vaughan, R.W. Hum. Immunol. (2003) [Pubmed]
  24. Decannulation and outcome following pediatric tracheostomy. Leung, R., Berkowitz, R.G. The Annals of otology, rhinology, and laryngology. (2005) [Pubmed]
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