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Gene Review

KLRC1  -  killer cell lectin-like receptor subfamily...

Homo sapiens

Synonyms: CD159 antigen-like family member A, CD159A, CD159a, NK cell receptor A, NKG2, ...
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Disease relevance of KLRC1


High impact information on KLRC1

  • Because Qa-1 also binds to self Qdm peptides that trigger NK (CD94/ NKG2) receptors on CD8(+) T cells, the machinery for homeostatic regulation of regulatory CD8(+) T cells can be envisioned [6].
  • A subset of HLA class I alleles has been shown to inhibit killing by CD94/NKG2A+ NK-cell clones [7].
  • These molecular adaptations make HLA-E a rigorous checkpoint at the cell surface reporting on the integrity of the antigen processing pathway to CD94/NKG2 receptor-bearing natural killer cells [8].
  • The lysis of melanoma cells by patient-derived CTLs was inhibited by the NK receptor CD94/NKG2A [9].
  • The induction of an inhibitory signal is consistent with the presence of two immunoreceptor tyrosine-based inhibitory motifs (V/LXYXXL) on the cytoplasmic domain of NKG2A [10].

Biological context of KLRC1

  • NKG2-A and -B peptides appear to be alternative splicing products of a single gene [11].
  • Peptide sequence homology searches demonstrate that the NKG2 peptides are members of a supergene family that includes several other type II membrane proteins [11].
  • DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells [11].
  • In the present communication, the original isolate, when used to probe a cDNA library prepared from a CD3- NK cell clone, was found to crosshybridize with a family of transcripts that fell into four distinct groups designated NKG2-A, -B, -C, and -D [11].
  • The NKG2 family of genes (HGMW-approved symbol KLRC) contains at least four members (NKG2-A, -C, -E, and -F) which are localized to human chromosome 12p12.3-p13 [12].

Anatomical context of KLRC1


Associations of KLRC1 with chemical compounds

  • NKG2A/B possesses two immunoreceptor tyrosine-based inhibition motif (ITIM) sequences in its cytoplasmic domain, which may be responsible for the inhibitory function of these receptors, whereas other NKG2 proteins lack ITIMs and may potentially transmit positive signals [17].
  • We show here that engagement of the CD94-NKG2A heterodimer inhibits both antigen-driven tumor necrosis factor (TNF) release and cytotoxicity on melanoma-specific human T cell clones [18].
  • The human CD94 glycoprotein covalently assembles with different C-type lectins of the NKG2 family [19].
  • In agreement with this result, the Y8F/Y40F mutant was unable to inhibit FcepsilonRI-mediated serotonin release and the Y8F mutant was relatively ineffective compared with wt NKG2A [20].
  • Conversely, retinoic acid produced by the intestinal dendritic cells may suppress NKG2A expression [21].

Physical interactions of KLRC1

  • CD94-T4/NKG2B is capable of binding HLA-E and, when expressed in E6-1 Jurkat T cells, inhibits TCR mediated signals, demonstrating that this heterodimer is functional [22].
  • There appears to be a strong, direct correlation between the binding affinity of the peptide-HLA-E complexes for the CD94/NKG2 receptors and the triggering of a response by the NK cell [23].
  • Using chromatin immunoprecipitation assays, we showed that GATA-3 specifically binds to the NKG2A promoter in situ in NKL and primary NK cells, but not in Jurkat T cells [24].

Regulatory relationships of KLRC1

  • NKG2-D was expressed in nine of fourteen T-cell clones or lines in the panel, whereas NKG2-A/B was expressed in three and NKG2-C was expressed in only one [25].
  • Similar to NK cells, most CD8 T cells that express high levels of CD94 co-express NKG2A, the inhibitory isoform [26].
  • It was possible to implicate the CD94/NKG2A complex as an inhibitory receptor recognizing this class Ib molecule by using as target a .221 transfectant selectively expressing surface HLA-E [27].
  • Taken together, our data indicate that GATA-3 is an important transcription factor for regulating NKG2A gene expression [24].
  • Interferon-alpha stimulates expression of stimulatory NKG2D receptors and inhibits the expression of inhibitory NKG2A receptors on NK cells [28].

Other interactions of KLRC1

  • Such stress induced peptide interference would gradually uncouple CD94/NKG2A inhibitory recognition and provide a mechanism for NK cells to detect stressed cells in a peptide-dependent manner [13].
  • Despite the similarities with the other NKG2 genes, NKG2-F encodes a putative protein which does not contain any lectin domain [29].
  • Thus, the data obtained reveal a substantial variability in the NKG2 repertoire among NK cell subpopulations, which is likely to affect the sensitivity and reactivity towards the ligand HLA-E [30].
  • Role for NKG2-A and NKG2-C surface receptors in chronic CD4+ T-cell responses [31].
  • We have developed a quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) assay designed to determine specific and absolute mRNA levels for NKG2-A/B, -C, -E, -F, -H and NKG2-D [30].

Analytical, diagnostic and therapeutic context of KLRC1


  1. Variations of human killer cell lectin-like receptors: common occurrence of NKG2-C deletion in the general population. Hikami, K., Tsuchiya, N., Yabe, T., Tokunaga, K. Genes Immun. (2003) [Pubmed]
  2. Negative regulation of NK cell activities by inhibitory receptor CD94/NKG2A leads to altered NK cell-induced modulation of dendritic cell functions in chronic hepatitis C virus infection. Jinushi, M., Takehara, T., Tatsumi, T., Kanto, T., Miyagi, T., Suzuki, T., Kanazawa, Y., Hiramatsu, N., Hayashi, N. J. Immunol. (2004) [Pubmed]
  3. Differential expression of inhibitory or activating CD94/NKG2 subtypes on MART-1-reactive T cells in vitiligo versus melanoma: a case report. Pedersen, L.Ø., Vetter, C.S., Mingari, M.C., Andersen, M.H., thor Straten, P., Bröcker, E.B., Becker, J.C. J. Invest. Dermatol. (2002) [Pubmed]
  4. Functional inhibitory human leucocyte antigen class I receptors on natural killer (NK) cells in patients with chronic NK lymphocytosis. Warren, H.S., Christiansen, F.T., Witt, C.S. Br. J. Haematol. (2003) [Pubmed]
  5. IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism. Malmberg, K.J., Levitsky, V., Norell, H., de Matos, C.T., Carlsten, M., Schedvins, K., Rabbani, H., Moretta, A., Söderström, K., Levitskaya, J., Kiessling, R. J. Clin. Invest. (2002) [Pubmed]
  6. The specific regulation of immune responses by CD8+ T cells restricted by the MHC class Ib molecule, Qa-1. Jiang, H., Chess, L. Annu. Rev. Immunol. (2000) [Pubmed]
  7. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Braud, V.M., Allan, D.S., O'Callaghan, C.A., Söderström, K., D'Andrea, A., Ogg, G.S., Lazetic, S., Young, N.T., Bell, J.I., Phillips, J.H., Lanier, L.L., McMichael, A.J. Nature (1998) [Pubmed]
  8. Structural features impose tight peptide binding specificity in the nonclassical MHC molecule HLA-E. O'Callaghan, C.A., Tormo, J., Willcox, B.E., Braud, V.M., Jakobsen, B.K., Stuart, D.I., McMichael, A.J., Bell, J.I., Jones, E.Y. Mol. Cell (1998) [Pubmed]
  9. In vivo expression of natural killer cell inhibitory receptors by human melanoma-specific cytolytic T lymphocytes. Speiser, D.E., Pittet, M.J., Valmori, D., Dunbar, R., Rimoldi, D., Liénard, D., MacDonald, H.R., Cerottini, J.C., Cerundolo, V., Romero, P. J. Exp. Med. (1999) [Pubmed]
  10. NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. Brooks, A.G., Posch, P.E., Scorzelli, C.J., Borrego, F., Coligan, J.E. J. Exp. Med. (1997) [Pubmed]
  11. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. Houchins, J.P., Yabe, T., McSherry, C., Bach, F.H. J. Exp. Med. (1991) [Pubmed]
  12. Sequence analysis of a 62-kb region overlapping the human KLRC cluster of genes. Plougastel, B., Trowsdale, J. Genomics (1998) [Pubmed]
  13. A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition. Michaëlsson, J., Teixeira de Matos, C., Achour, A., Lanier, L.L., Kärre, K., Söderström, K. J. Exp. Med. (2002) [Pubmed]
  14. Orderly and nonstochastic acquisition of CD94/NKG2 receptors by developing NK cells derived from embryonic stem cells in vitro. Lian, R.H., Maeda, M., Lohwasser, S., Delcommenne, M., Nakano, T., Vance, R.E., Raulet, D.H., Takei, F. J. Immunol. (2002) [Pubmed]
  15. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. Borrego, F., Ulbrecht, M., Weiss, E.H., Coligan, J.E., Brooks, A.G. J. Exp. Med. (1998) [Pubmed]
  16. NK cell CD94/NKG2A inhibitory receptors are internalized and recycle independently of inhibitory signaling processes. Borrego, F., Kabat, J., Sanni, T.B., Coligan, J.E. J. Immunol. (2002) [Pubmed]
  17. Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. Lazetic, S., Chang, C., Houchins, J.P., Lanier, L.L., Phillips, J.H. J. Immunol. (1996) [Pubmed]
  18. Inhibition of antigen-induced T cell response and antibody-induced NK cell cytotoxicity by NKG2A: association of NKG2A with SHP-1 and SHP-2 protein-tyrosine phosphatases. Le Dréan, E., Vély, F., Olcese, L., Cambiaggi, A., Guia, S., Krystal, G., Gervois, N., Moretta, A., Jotereau, F., Vivier, E. Eur. J. Immunol. (1998) [Pubmed]
  19. The CD94/NKG2 C-type lectin receptor complex: involvement in NK cell-mediated recognition of HLA class I molecules. López-Botet, M., Carretero, M., Pérez-Villar, J., Bellón, T., Llano, M., Navarro, F. Immunol. Res. (1997) [Pubmed]
  20. Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays in mediating the human CD94/NKG2A inhibitory signal. Kabat, J., Borrego, F., Brooks, A., Coligan, J.E. J. Immunol. (2002) [Pubmed]
  21. Cutting Edge: Distinct NK Receptor Profiles Are Imprinted on CD8 T Cells in the Mucosa and Periphery during the Same Antigen Challenge: Role of Tissue-Specific Factors. Laouar, A., Manocha, M., Wan, M., Yagita, H., van Lier, R.A., N, M. J. Immunol. (2007) [Pubmed]
  22. The human CD94 gene encodes multiple, expressible transcripts including a new partner of NKG2A/B. Lieto, L.D., Maasho, K., West, D., Borrego, F., Coligan, J.E. Genes Immun. (2006) [Pubmed]
  23. Kinetics and peptide dependency of the binding of the inhibitory NK receptor CD94/NKG2-A and the activating receptor CD94/NKG2-C to HLA-E. Valés-Gómez, M., Reyburn, H.T., Erskine, R.A., López-Botet, M., Strominger, J.L. EMBO J. (1999) [Pubmed]
  24. GATA-3 is an important transcription factor for regulating human NKG2A gene expression. Marusina, A.I., Kim, D.K., Lieto, L.D., Borrego, F., Coligan, J.E. J. Immunol. (2005) [Pubmed]
  25. A multigene family on human chromosome 12 encodes natural killer-cell lectins. Yabe, T., McSherry, C., Bach, F.H., Fisch, P., Schall, R.P., Sondel, P.M., Houchins, J.P. Immunogenetics (1993) [Pubmed]
  26. The role of CD94/NKG2 in innate and adaptive immunity. Gunturi, A., Berg, R.E., Forman, J. Immunol. Res. (2004) [Pubmed]
  27. HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Lee, N., Llano, M., Carretero, M., Ishitani, A., Navarro, F., López-Botet, M., Geraghty, D.E. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  28. Opposing effect of IFNgamma and IFNalpha on expression of NKG2 receptors: negative regulation of IFNgamma on NK cells. Zhang, C., Zhang, J., Sun, R., Feng, J., Wei, H., Tian, Z. Int. Immunopharmacol. (2005) [Pubmed]
  29. Cloning of NKG2-F, a new member of the NKG2 family of human natural killer cell receptor genes. Plougastel, B., Trowsdale, J. Eur. J. Immunol. (1997) [Pubmed]
  30. Differential expression of inhibitory and activating CD94/NKG2 receptors on NK cell clones. Brostjan, C., Bellón, T., Sobanov, Y., López-Botet, M., Hofer, E. J. Immunol. Methods (2002) [Pubmed]
  31. Role for NKG2-A and NKG2-C surface receptors in chronic CD4+ T-cell responses. Ortega, C., Romero, P., Palma, A., Orta, T., Peña, J., García-Vinuesa, A., Molina, I.J., Santamaría, M. Immunol. Cell Biol. (2004) [Pubmed]
  32. The human natural killer gene complex is located on chromosome 12p12-p13. Renedo, M., Arce, I., Rodríguez, A., Carretero, M., Lanier, L.L., López-Botet, M., Fernández-Ruiz, E. Immunogenetics (1997) [Pubmed]
  33. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. Nguyen, S., Dhedin, N., Vernant, J.P., Kuentz, M., Al Jijakli, A., Rouas-Freiss, N., Carosella, E.D., Boudifa, A., Debré, P., Vieillard, V. Blood (2005) [Pubmed]
  34. The activating form of CD94 receptor complex: CD94 covalently associates with the Kp39 protein that represents the product of the NKG2-C gene. Cantoni, C., Biassoni, R., Pende, D., Sivori, S., Accame, L., Pareti, L., Semenzato, G., Moretta, L., Moretta, A., Bottino, C. Eur. J. Immunol. (1998) [Pubmed]
  35. Effect of tumor growth factor-beta on NK receptor expression by allostimulated CD8+ T lymphocytes. Guerra, N., Benlhassan, K., Carayol, G., Guillard, M., Pardoux, C., Chouaib, S., Caignard, A. Eur. Cytokine Netw. (1999) [Pubmed]
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