Disease relevance of KLRC1

• CD94 and NKG2 are members of the NK cell receptor families, and are encoded in the natural killer gene complex (NKC) on human chromosome 12p12-13, one of the candidate chromosomal regions for rheumatic diseases [1].
• 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 [2].
• Differential expression of inhibitory or activating CD94/NKG2 subtypes on MART-1-reactive T cells in vitiligo versus melanoma: a case report [3].
• Inhibitory HLA class I receptors silence NK cells against cells expressing normal levels of HLA class I. Analysis of NK cells in six patients with chronic NK lymphocytosis revealed a high level of the inhibitory CD94/NKG2A receptor on all NK cells [4].
• IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism [5].

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

• We have previously described the isolation of a cDNA clone, designated NKG2, that was expressed in all natural killer (NK) cells tested but not in T or B cells [11].
• It interacts with CD94/NKG2 receptors expressed on the surface of natural killer (NK) cells and T cell subsets [13].
• Orderly and nonstochastic acquisition of CD94/NKG2 receptors by developing NK cells derived from embryonic stem cells in vitro [14].
• 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 [15].
• We have analyzed the cellular trafficking of the CD94/NKG2A receptor using the NKL cell line and peripheral blood NK cells [16].

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

• Sequence analysis of a 62-kb region overlapping the human KLRC cluster of genes [12].
• Here we report the assignment by fluorescence in situ hybridization of the CD94 gene to human chromosome 12p12-p13, in the same region where the CD69 and NKG2A genes had been previously mapped [32].
• NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect [33].
• Peptide mapping analysis indicates that Kp39 and NKG2-A glycoproteins belong to the same molecular family [34].
• Using PCR, we also demonstrated that TGF-beta had no effect on the transcription of non-inhibitory NKG2 molecules [35].

References