Alternative titles; symbols
HGNC Approved Gene Symbol: NCR1
Cytogenetic location: 19q13.42 Genomic coordinates (GRCh38) : 19:54,898,198-54,938,208 (from NCBI)
Natural killer (NK) cells mediate MHC nonrestricted cytotoxicity. There are many candidate molecules for NK cell recognition structures, including inhibiting and activating receptors. Using a monoclonal antibody capable of triggering NK-mediated lysis, Sivori et al. (1997) identified a cell surface molecule of 46 kD that they termed p46. The molecule lacks N-linked sugars and is expressed on resting and activated NK cells but not on T cells or B cells. In addition to lytic activity, monoclonal antibody-mediated crosslinking induces intracellular calcium increases and cytokine production.
By screening a human NK cell cDNA library, Pessino et al. (1998) cloned the cDNA for NKp46, or LY94, an Ig superfamily member that may cooperate with other activating receptors (e.g., LY95, 604531). The LY94 cDNA encodes a 304-amino acid type I transmembrane protein. The extracellular region is preceded by a 21-residue signal peptide with 2 cysteine-bridged C2-type Ig-like domains. A stem connects the extracellular domain to the apparently short transmembrane domain of 19 amino acids, which includes an arginine. The intracellular region contains 30 amino acids and is rich in basic residues, but does not contain any immunoreceptor tyrosine-based activating motifs (ITAM). LY94 appears to associate with the ITAM-containing CD3-zeta (CD3Z; 186780) subunit. When LY94 is expressed in COS-7 cells, anti-NKp46 immunoprecipitates a 46-kD surface molecule. Northern blot analysis revealed weak expression of a major transcript of 3.4 kb in spleen but in no other human tissue. Further analysis, with RT-PCR confirmation, in various lymphoid and myelomonocytic cells revealed that LY94 expression is confined to NK cells.
Exposure to Mycobacterium tuberculosis often results in infection manifested by a T-cell-dependent positive tuberculin skin test (TST). However, some individuals who have had prolonged exposure do not develop a positive TST, suggesting that innate immunity mediated by NK cells may control the infection. Vankayalapati et al. (2002) showed that NK cells expressing NKP46, but not those expressing NKP44, from healthy TST-positive and TST-negative donors efficiently lysed M. tuberculosis-infected autologous monocytes in an apparently cytokine-independent manner. In contrast, NK cells from tuberculosis patients mediated significantly less lysis against such cells or against K562 erythroleukemia cells, in spite of having comparable numbers of circulating CD56 (116930)-positive NK cells. Infection of monocytes did not result in reduced expression of MHC class I molecules, and NK-cell lytic activity was not due to an observed enhanced production of interleukin-18 (IL18; 600953) or gamma-interferon (IFNG; 147570) by donor NK cells. RT-PCR analysis revealed upregulated NKP46, but not NKP44, expression after exposure to M. tuberculosis-infected monocytes by healthy donors, but not by tuberculosis patients. NK-cell cytotoxic activity could be blocked by anti-NKP46 without affecting cell viability. Vankayalapati et al. (2002) concluded that NKP46 participates in NK-cell-mediated lysis of cells infected with an intracellular bacterium and that reduced functional capacity of NK cells is associated with severe manifestations of infectious disease.
By somatic cell hybrid analysis, Pessino et al. (1998) mapped the LY94 gene to chromosome 19, where genes encoding other NK inhibitory and activator structures are also located.
Gazit et al. (2006) found that replacing the Ncr1 gene with a green fluorescent protein reporter cassette resulted in enhanced tumor spread in 129/Sv mice, but not in C57BL/6 mice. However, influenza infection was lethal in both strains, despite accumulation of NK cells at the site of infection. Gazit et al. (2006) concluded that NCR1 is essential for eradication of influenza virus.
Using chemical mutagenesis of mice, Narni-Mancinelli et al. (2012) identified an autosomal recessive mutation resulting in a phenotype, termed Noe, characterized by increased resistance to viral infections due to the presence of hyperresponsive NK cells. Whole genome sequencing and functional analysis revealed a loss-of-function mutation in the Ncr1 gene. Although Gazit et al. (2006) reported that Ncr1-knockout mice were highly susceptible to H1N1PR8 influenza infection, Narni-Mancinelli et al. (2012) found that mice with the Noe phenotype were more resistant to H1N1PR8 and had a higher frequency of NK cells producing Ifng than wildtype mice. As an explanation for this discrepancy, Narni-Mancinelli et al. (2012) suggested that deletion of 3 intronic microRNAs, Mir1195, Mir1935, and Mir3470a, may have been responsible for the phenotype in Ncr1-knockout mice reported by Gazit et al. (2006). Narni-Mancinelli et al. (2012) found that downregulation of NK-cell activity by Ncr1 was associated with silencing of the Helios (IKZF2; 606234) transcription factor in NK cells. Ncr1 was critical for the subsequent development of antiviral and antibacterial T-cell responses, suggesting that regulation of NK-cell function by Ncr1 allows for optimal development of adaptive immunity. The Noe phenotype could be mimicked by antibody blockade of wildtype Ncr1. Narni-Mancinelli et al. (2012) proposed that NCR1 blockade may be useful as an immunotherapeutic strategy to enhance NK-cell effector function, particularly in patients with T-cell deficiencies.
Gazit, R., Gruda, R., Elboim, M., Arnon, T. I., Katz, G., Achdout, H., Hanna, J., Qimron, U., Landau, G., Greenbaum, E., Zakay-Rones, Z., Porgador, A., Mandelboim, O. Lethal influenza infection in the absence of the natural killer cell receptor gene Ncr1. Nature Immun. 7: 517-523, 2006. [PubMed: 16565719] [Full Text: https://doi.org/10.1038/ni1322]
Narni-Mancinelli, E., Jaeger, B. N., Bernat, C., Fenis, A., Kung, S., De Gassart, A., Mahmood, S., Gut, M., Heath, S. C., Estelle, J., Bertosio, E., Vely, F., Gastinel, L. N., Beutler, B., Malissen, B., Malissen, M., Gut, I. G., Vivier, E., Ugolini, S. Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses. Science 335: 344-348, 2012. [PubMed: 22267813] [Full Text: https://doi.org/10.1126/science.1215621]
Pessino, A., Sivori, S., Bottino, C., Malaspina, A., Morelli, L., Moretta, L., Biassoni, R., Moretta, A. Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J. Exp. Med. 188: 953-960, 1998. [PubMed: 9730896] [Full Text: https://doi.org/10.1084/jem.188.5.953]
Sivori, S., Vitale, M., Morelli, L., Sanseverino, L., Augugliaro, R., Bottino, C., Moretta, L., Moretta, A. p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J. Exp. Med. 186: 1129-1136, 1997. [PubMed: 9314561] [Full Text: https://doi.org/10.1084/jem.186.7.1129]
Vankayalapati, R., Wizel, B., Weis, S. E., Safi, H., Lakey, D. L., Mandelboim, O., Samten, B., Porgador, A., Barnes, P. F. The NKp46 receptor contributes to NK cell lysis of mononuclear phagocytes infected with an intracellular bacterium. J. Immun. 168: 3451-3457, 2002. [PubMed: 11907104] [Full Text: https://doi.org/10.4049/jimmunol.168.7.3451]