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HGNC Approved Gene Symbol: KLRC1
Cytogenetic location: 12p13.2 Genomic coordinates (GRCh38): 12:10,442,264-10,454,685 (from NCBI)
Houchins et al. (1991) reported the cDNA sequences of a series of related transcripts, including NKG2A and NKG2B, that are expressed primarily in natural killer (NK) cells. NKG2A and NKG2B appeared to be alternative splicing products of a single gene.
Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. NK cells preferentially express several calcium-dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. Houchins et al. (1991) reported the cDNA sequences of a series of related transcripts that are expressed primarily in NK cells. This group, designated NKG2, encodes a family of transmembrane proteins characterized by the unusual type II membrane orientation (extracellular C terminus) and the presence of a C-type lectin domain. This family is characterized by at least 5 distinct transcripts, designated NKG2A, B, C (602891), D (611897), and E (602892) (Houchins et al., 1991; Adamkiewicz et al., 1994). The DNA sequences suggested that 2 of these, NKG2A and NKG2B, are alternative splicing products of a single gene, but that the other transcripts are products of different genes. Yabe et al. (1993) used transcript-specific probe fragments to study these genes further. The predicted peptides shared sequence similarity with known receptor molecules. Southern blot experiments demonstrated that at high stringency the probes cross-hybridized with a maximum of 5 genes. By study of hamster/human hybrid somatic cell lines, they demonstrated that all of the hybridizing fragments were located on human chromosome 12. Each of the transcripts occurred in all 3 of the NK cell lines tested; however, the genes were differentially regulated in T cells. The limited distribution of these proteins and their sequence similarity with known receptor molecules suggested that they may function as receptors on human NK cells.
Plougastel et al. (1996) isolated a cosmid containing the human NKG2A gene. They found that the NKG2A gene is encoded by 7 exons spanning 25 kb. The nucleotides of exon 5 were absent in some reported cDNA sequences, consistent with differential splicing. Using 5-prime RACE, Plougastel and Trowsdale (1998) determined that there are 2 alternative NKG2A transcription start sites. Although both classes of transcripts appear to encode the same protein, the larger mRNA has a noncoding leader exon.
Plougastel et al. (1996) used fluorescence in situ hybridization to map the NKG2A gene to chromosome 12p13.1-p12.3. By analysis of YAC and cosmid contigs, Renedo et al. (1997) and Plougastel and Trowsdale (1998) found that NKG2 gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed on NK cells. The NK complex spans 0.7-2.4 Mb and is arranged NKRP1A (KLRB1; 602890)--CD69 (107273)--AICL (603242)--NKG2C (KLRC2; 602891)/NKG2A--NKG2E (KLRC3; 602892)-- NKG2F/NKG2D (KLRC4; 602893)--CD94 (KLRD1; 602894). Plougastel and Trowsdale (1998) found that the NKG2 gene family members and CD94 are clustered within 350 kb. They stated that the mouse NK gene complex (NKC) is located on mouse chromosome 6 in a region showing homology of synteny with human chromosome 12.
In a review of immune inhibitory receptors, Ravetch and Lanier (2000) pointed out that autoimmune disorders may result from the disruption of inhibitory receptors, particularly in their conserved intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs). ITIMs are sites for alternative phosphorylation, typically by a Src kinase, and dephosphorylation, either by the tyrosine phosphatase SHP1 (176883) or the inositol phosphatase SHIP (601582), transducing signals to distinct pathways. Ravetch and Lanier (2000) noted that NKG2A has 2 ITIMs that interact with SHP1 or SHP2 (176876). NKG2A is typically expressed on about half of all NK cells as well as on a subset of CD8+ T cells. NKG2A recognizes HLA-E (143010), thereby providing a mechanism for NK or T cells expressing NKG2A to monitor expression of MHC class I on tissues.
The protein HLA-E is a nonclassical MHC molecule of limited sequence variability. Its expression on the cell surface is regulated by the binding of peptides derived from the signal sequence of some other MHC class I molecules. Braud et al. (1998) reported the identification of ligands for HLA-E. Braud et al. (1998) constructed tetramers in which recombinant HLA-E and beta-2 microglobulin were refolded with an MHC leader-sequence peptide, biotinylated, and conjugated to Extravidin. This HLA-E tetramer bound to natural killer (NK) cells and a small subset of T cells from peripheral blood. On transfectants, the tetramer bound to the CD94/NKG2A, CD94/NKG2B, and CD94/NKG2C NK cell receptors, but did not bind to the immunoglobulin family of NK cell receptors (KIRs; see 604936). Surface expression of HLA-E was enough to protect target cells from lysis by CD94/NKG2A+ NK cell clones. A subset of HLA class I alleles had been shown to inhibit killing by CD94/NKG2A+ NK cell clones. Only the HLA alleles that possess a leader peptide capable of upregulating HLA-E surface expression confer resistance to NK cell-mediated lysis, implying that their action is mediated by HLA-E, the predominant ligand for the NK cell inhibitory receptor CD94/NKG2A.
Ramsuran et al. (2018) analyzed 9,763 HIV-infected individuals from 21 cohorts and found that higher HLA-A (142800) levels confer poorer control of HIV. Elevated HLA-A expression provides enhanced levels of an HLA-A-derived signal peptide that specifically binds and determines expression levels of HLA-E, the ligand for the inhibitory NKG2A natural killer cell receptor. HLA-B (142830) haplotypes that favor NKG2A-mediated NK cell licensing (i.e., education) exacerbate the deleterious effect of high HLA-A on HIV control, consistent with NKG2A-mediated inhibition impairing NK cell clearance of HIV-infected targets.
Rapaport et al. (2015) deleted Klrc1 in mice without disrupting transcription of Klrc2 or Klrc3. Klrc1 deletion had no effect on frequencies of T, NKT, and NK cells or on maturity of NK cells. Klrc1 -/- mice had an impaired response to infection with ectromelia virus (ECTV), but not lymphocytic choriomeningitis, vesicular stomatitis virus, or vaccinia virus. ECTV-specific Klrc1 -/- Cd8 (see 186910)-positive cells showed excessive activation and greater apoptosis compared with wildtype. Rapaport et al. (2015) concluded that Klrc1 optimizes Cd8-positive T-cell responses during ECTV infection.
Adamkiewicz, T. V., McSherry, C., Bach, F. H., Houchins, J. P. Natural killer lectin-like receptors have divergent carboxy-termini, distinct from C-type lectins. Immunogenetics 39: 218 only, 1994. Note: Erratum: Immunogenetics 40: 318 only, 1994. [PubMed: 8276468] [Full Text: https://doi.org/10.1007/BF00241264]
Braud, V. M., Allan, D. S. J., O'Callaghan, C. A., Soderstrom, K., D'Andrea, A., Ogg, G. S., Lazetic, S., Young, N. T., Bell, J. I., Phillips, J. H., Lanier, L. L., McMichael, A. J. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391: 795-799, 1998. [PubMed: 9486650] [Full Text: https://doi.org/10.1038/35869]
Houchins, J. P., Yabe, T., McSherry, C., Bach, F. H. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. J. Exp. Med. 173: 1017-1020, 1991. [PubMed: 2007850] [Full Text: https://doi.org/10.1084/jem.173.4.1017]
Plougastel, B., Jones, T., Trowsdale, J. Genomic structure, chromosome location, and alternative splicing of the human NKG2A gene. Immunogenetics 44: 286-291, 1996. [PubMed: 8753859] [Full Text: https://doi.org/10.1007/BF02602558]
Plougastel, B., Trowsdale, J. Sequence analysis of a 62-kb region overlapping the human KLRC cluster of genes. Genomics 49: 193-199, 1998. [PubMed: 9598306] [Full Text: https://doi.org/10.1006/geno.1997.5197]
Ramsuran, V., Naranbhai, V., Horowitz, A., Qi, Y., Martin, MP., Yuki, Y., Gao, X., Walker-Sperling, V., Del Prete, G. Q., Schneider, D. K., Lifson, J. D., Fellay, J., and 14 others. Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells. Science 359: 86-90, 2018. Note: Erratum: Science 365 (6452), 2019. [PubMed: 29302013] [Full Text: https://doi.org/10.1126/science.aam8825]
Rapaport, A. S., Schriewer, J., Gilfillan, S., Hembrador, E., Crump, R., Plougastel, B. F., Wang, Y., Le Friec, G., Gao, J., Cella, M., Pircher, H., Yokoyama, W. M., Buller, R. M. L., Colonna, M. The inhibitory receptor NKG2A sustains virus-specific CD8+ T cells in response to a lethal poxvirus infection. Immunity 43: 1112-1124, 2015. [PubMed: 26680205] [Full Text: https://doi.org/10.1016/j.immuni.2015.11.005]
Ravetch, J. V., Lanier, L. L. Immune inhibitory receptors. Science 290: 84-89, 2000. [PubMed: 11021804] [Full Text: https://doi.org/10.1126/science.290.5489.84]
Renedo, M., Arce, I., Rodriguez, A., Carretero, M., Lanier, L. L., Lopez-Botet, M., Fernandez-Ruiz, E. The human natural killer gene complex is located on chromosome 12p12-p13. Immunogenetics 46: 307-311, 1997. [PubMed: 9218532] [Full Text: https://doi.org/10.1007/s002510050276]
Yabe, T., McSherry, C., Bach, F. H., Fisch, P., Schall, R. P., Sondel, P. M., Houchins, J. P. A multigene family on human chromosome 12 encodes natural killer-cell lectins. Immunogenetics 37: 455-460, 1993. [PubMed: 8436421] [Full Text: https://doi.org/10.1007/BF00222470]