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Gene Review

KIR2DL4  -  killer cell immunoglobulin-like receptor,...

Homo sapiens

Synonyms: 103AS, 15.212, CD158 antigen-like family member D, CD158D, G9P, ...
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Disease relevance of KIR2DL4


High impact information on KIR2DL4

  • Killer immunoglobulin-like receptors (KIR) bind self-major histocompatibility complex class I molecules, allowing natural killer (NK) cells to recognize aberrant cells that have down-regulated class I. NK cells express variable numbers and combinations of highly homologous clonally restricted KIR genes, but uniformly express KIR2DL4 [3].
  • Here we show that recombinant soluble KIR2DL4 binds to cells expressing HLA-G but not to cells expressing other HLA class I molecules [4].
  • Furthermore, functional transfer of KIR2DL4 into the cell line NK-92 resulted in inhibition of lysis of target cells that express HLA-G, but not target cells that express other class I molecules including HLA-E [4].
  • Unlike other HLA class I-specific KIRs, which are clonally distributed on NK cells, KIR2DL4 is expressed at the surface of all NK cells [4].
  • Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig-like receptors (KIR), of KIR2DL4, and of KIR3DL3 [5].

Biological context of KIR2DL4


Anatomical context of KIR2DL4

  • Therefore, given that HLA-G expression is restricted to fetal trophoblast cells, KIR2DL4 may provide important signals to maternal NK decidual cells that interact with trophoblast cells at the maternal-fetal interface during pregnancy [4].
  • Killer cell immunoglobulin-like receptors (KIRs) recognize groups of human leukocyte antigen (HLA) class Ia proteins displaying common structural features at the alpha-1 domain; among them, KIR2DL4 has been proposed to specifically interact with the class Ib molecule HLA-G1 [11].
  • This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy [8].

Associations of KIR2DL4 with chemical compounds

  • Mutated forms of KIR2DL4 were engineered that lacked either the tyrosine in the ITIM or an arginine-tyrosine motif in the transmembrane region that is required for the activation signal [12].
  • The KIR3DH molecules have three Ig domains, transmembrane domains homologous to KIR2DL4 molecules that contain an arginine, and short cytoplasmic domains [13].

Other interactions of KIR2DL4

  • In NK cells, reporter gene expression driven by the KIR2DL4 promoter was greater than that driven by the KIR3DL1 promoter [6].
  • KIR2DL5 has two extracellular Ig-like domains of the D0 and D2 type, a structural configuration that was previously unique to KIR2DL4 [14].
  • In pull-down experiments with GST fusion proteins, the tyrosine-phosphorylated cytoplasmic tail of KIR2DL4 bound the Src homology 2-containing phosphatases 1 and 2, as did the tail of the inhibitory receptor KIR2DL1 [12].
  • Conversely, it expresses few inhibitory receptors (NKGA/B, low levels of KIR2DL4, ILT-2), lacking most of the killer inhibitory receptors (KIRs) clonally expressed on normal NK cells [15].
  • KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential [12].

Analytical, diagnostic and therapeutic context of KIR2DL4


  1. Alleles of the KIR2DL4 receptor and their lack of association with pre-eclampsia. Witt, C.S., Whiteway, J.M., Warren, H.S., Barden, A., Rogers, M., Martin, A., Beilin, L., Christiansen, F.T. Eur. J. Immunol. (2002) [Pubmed]
  2. Residues Met76 and Gln79 in HLA-G alpha1 domain involve in KIR2DL4 recognition. Yan, W.H., Fan, L.A. Cell Res. (2005) [Pubmed]
  3. DNA methylation maintains allele-specific KIR gene expression in human natural killer cells. Chan, H.W., Kurago, Z.B., Stewart, C.A., Wilson, M.J., Martin, M.P., Mace, B.E., Carrington, M., Trowsdale, J., Lutz, C.T. J. Exp. Med. (2003) [Pubmed]
  4. A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells. Rajagopalan, S., Long, E.O. J. Exp. Med. (1999) [Pubmed]
  5. Three structurally and functionally divergent kinds of promoters regulate expression of clonally distributed killer cell Ig-like receptors (KIR), of KIR2DL4, and of KIR3DL3. Trompeter, H.I., Gómez-Lozano, N., Santourlidis, S., Eisermann, B., Wernet, P., Vilches, C., Uhrberg, M. J. Immunol. (2005) [Pubmed]
  6. Different and divergent regulation of the KIR2DL4 and KIR3DL1 promoters. Stewart, C.A., Van Bergen, J., Trowsdale, J. J. Immunol. (2003) [Pubmed]
  7. Recognition of HLA-G by the NK cell receptor KIR2DL4 is not essential for human reproduction. Gómez-Lozano, N., de Pablo, R., Puente, S., Vilches, C. Eur. J. Immunol. (2003) [Pubmed]
  8. Activation of NK cells by an endocytosed receptor for soluble HLA-G. Rajagopalan, S., Bryceson, Y.T., Kuppusamy, S.P., Geraghty, D.E., van der Meer, A., Joosten, I., Long, E.O. PLoS Biol. (2006) [Pubmed]
  9. KIR2DL4 (CD158d) genotype influences expression and function in NK cells. Goodridge, J.P., Witt, C.S., Christiansen, F.T., Warren, H.S. J. Immunol. (2003) [Pubmed]
  10. The genomic context of natural killer receptor extended gene families. Trowsdale, J., Barten, R., Haude, A., Stewart, C.A., Beck, S., Wilson, M.J. Immunol. Rev. (2001) [Pubmed]
  11. Paired inhibitory and triggering NK cell receptors for HLA class I molecules. López-Botet, M., Bellón, T., Llano, M., Navarro, F., García, P., de Miguel, M. Hum. Immunol. (2000) [Pubmed]
  12. KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential. Faure, M., Long, E.O. J. Immunol. (2002) [Pubmed]
  13. Diversity of the killer cell Ig-like receptors of rhesus monkeys. Hershberger, K.L., Shyam, R., Miura, A., Letvin, N.L. J. Immunol. (2001) [Pubmed]
  14. KIR2DL5, a novel killer-cell receptor with a D0-D2 configuration of Ig-like domains. Vilches, C., Rajalingam, R., Uhrberg, M., Gardiner, C.M., Young, N.T., Parham, P. J. Immunol. (2000) [Pubmed]
  15. Factors regulating the cytotoxic activity of the human natural killer cell line, NK-92. Maki, G., Klingemann, H.G., Martinson, J.A., Tam, Y.K. J. Hematother. Stem Cell Res. (2001) [Pubmed]
  16. Investigation of killer cell immunoglobulin-like receptor KIR2DL4 diversity by sequence-based typing in Chinese population. Zhu, F.M., Jiang, K., Lv, Q.F., He, J., Yan, L.X. Tissue Antigens (2006) [Pubmed]
  17. Detection of KIR2DL4 alleles by sequencing and SSCP reveals a common allele with a shortened cytoplasmic tail. Witt, C.S., Martin, A., Christiansen, F.T. Tissue Antigens (2000) [Pubmed]
  18. Homogenous expression of killer cell immunoglobulin-like receptors (KIR) on polyclonal natural killer cells detected by a monoclonal antibody to KIR2D. Watzl, C., Peterson, M., Long, E.O. Tissue Antigens (2000) [Pubmed]
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