Key Points
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Natural killer (NK) cell function (cytotoxic activity and cytokine secretion) is regulated by a balance of signals transmitted by opposing activating and inhibitory receptors.
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Activating NK cell receptors use transmembrane adaptor proteins such as FcɛRIγ, CD3ζ and DAP12 to stimulate the ZAP70 and Syk tyrosine kinase pathways, and another transmembrane adaptor protein DAP10 to activate the phosphatidylinositol 3-kinase pathway.
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The activating NKG2D receptor binds to human major histocompatibility complex (MHC) class-I-chain-related A (MICA) and MICB proteins, encoded by genes within the MHC, and to glycoproteins that represent orthologues of the mouse retinoic acid early inducible (RAE-1) molecules.
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NK cells kill tumours expressing the MIC or RAE-1 ligands of the NKG2D receptor, even when the tumours express MHC class I molecules that are recognized by the inhibitory NK cell receptors.
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A role of NK cells in anti-viral immunity has been demonstrated most convincingly in protection against cytomegalovirus and other herpesviruses.
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Infection with human cytomegalovirus induces expression of MIC proteins, ligands of the activating NKG2D receptor.
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The mouse activating Ly49H receptor has been implicated in host resistance to mouse cytomegalovirus.
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Cytomegalovirus encodes several proteins that bind to MHC class I and MIC that might inhibit recognition by T cells and NK cells.
Abstract
Natural killer cells are innate immune cells that control certain microbial infections and tumours. The function of natural killer cells is regulated by a balance between signals transmitted by activating receptors, which recognize ligands on tumours and virus-infected cells, and inhibitory receptors specific for major histocompatibility complex class I molecules. Here, we review the emerging evidence that natural killer cells have an important role in vivo in immune defence.
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References
Trinchieri, G. Biology of natural killer cells. Adv. Immunol. 47, 187–376 (1989).
Smyth, M. J., Godfrey, D. I. & Trapani, J. A. A fresh look at tumor immunosurveillance and immunotherapy. Nature Immunol. 2, 293–299 (2001).Recent review summarizing evidence for tumour immunosurveillance and the role of natural killer cells and T cells.
Kärre, K., Ljunggren, H. G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defense strategy. Nature 319, 675–678 (1986).
Moretta, A. et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu. Rev. Immunol. 19, 197–223 (2001).A comprehensive review of the NKp30, NKp44 and NKp46 receptors and their potential role in tumour recognition.
Long, E. O. Regulation of immune responses through inhibitory receptors. Annu. Rev. Immunol. 17, 875–904 (1999).
Ravetch, J. V. & Lanier, L. L. Immune inhibitory receptors. Science 290, 84–89 (2000).A comprehensive review of the inhibitory immune receptors, including the MHC class I receptors that regulate natural killer cells and T-cell activation.
Leiden, J. M., Karpinski, B. A., Gottschalk, L. & Kornbluth, J. Susceptibility to natural killer cell-mediated cytolysis is independent of the level of target cell class I HLA expression. J. Immunol. 142, 2140–2147 (1989).
Nishimura, M. I., Stroynowski, I., Hood, L. & Ostrand-Rosenberg, S. H-2Kb antigen expression has no effect on natural killer susceptibility and tumorigenicity of a murine hepatoma. J. Immunol. 141, 4403–4409 (1988).
Pena, J. et al. Natural killer susceptibility is independent of HLA class I antigen expression on cell lines obtained from human solid tumors. Eur. J. Immunol. 20, 2445–2449 (1990).
Litwin, V., Gumperz, J., Parham, P., Phillips, J. H. & Lanier, L. L. Specificity of HLA class I antigen recognition by human NK clones: evidence for clonal heterogeneity, protection by self and non-self alleles, and influence of the target cell type. J. Exp. Med. 178, 1321–1336 (1993).
Lanier, L. L. On guard — activating NK cell receptors. Nature Immunol. 2, 23–27 (2001).
Moretta, L. et al. Existence of both inhibitory (p58) and activatory (p50) receptors for HLA-C molecules in human natural killer cells. J. Exp. Med. 182, 875–884 (1995).
Smith, K. M., Wu, J., Bakker, A. B. H., Phillips, J. H. & Lanier, L. L. Ly49D and Ly49H associate with mouse DAP12 and form activating receptors. J. Immunol. 161, 7–10 (1998).
Perussia, B. et al. The Fc receptor for IgG on human natural killer cells: phenotypic, functional, and comparative studies with monoclonal antibodies. J. Immunol. 133, 180–189 (1984).
Mandelboim, O. et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature 409, 1055–1060 (2001).Evidence that the activating natural killer cell receptor NKp46 is involved in anti-viral immunity.
Tomasello, E. et al. Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice. Immunity 13, 355–364 (2000).
Vitale, M. et al. NKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysis. J. Exp. Med. 187, 2065–2072 (1998).
Pessino, A. et al. Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J. Exp. Med. 188, 953–960 (1998).
Sivori, S. et al. NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. Eur. J. Immunol. 29, 1656–1666 (1999).
Cantoni, C. et al. NKp44, a triggering receptor involved in tumor cell lysis by activated human natural killer cells, is a novel member of the immunoglobulin superfamily. J. Exp. Med. 189, 787–796 (1999).
Pende, D. et al. Identification and molecular characterization of NKP30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J. Exp. Med. 190, 1505–1516 (1999).
Moretta, A., Biassoni, R., Bottino, C., Mingari, M. C. & Moretta, L. Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol. Today 21, 228–234 (2000).
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).
Bauer, S. et al. Activation of natural killer cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285, 727–730 (1999).Shows that the NKG2D receptor binds to the stress-induced MIC molecules and activates natural killer cells.
Wu, J. et al. An activating receptor complex on natural killer and T cells formed by NKG2D and DAP10. Science 285, 730–732 (1999).Shows that the NKG2D receptor signals through a transmembrane adaptor molecule activating the phosphatidylinositol 3-kinase pathway.
Wu, J., Cherwinski, H., Spies, T., Phillips, J. H. & Lanier, L. L. DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells. J. Exp. Med. 192, 1059–1068 (2000).
Wilson, M. J., Lindquist, J. A. & Trowsdale, J. DAP12 and KAP10 (DAP10) — novel transmembrane adapter proteins of the CD3ζ family. Immunol. Res. 22, 21–42 (2000).
Li, P. et al. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nature Immunol. 2, 443–451 (2001).Structure of the NKG2D receptor complexed with the MICA ligand.
Groh, V. et al. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl Acad. Sci. USA 93, 12445–12450 (1996).Reports that the MIC genes are regulated by stress and that MIC-bearing cells are recognized by γδ-TcR+ T cells.
Groh, V. et al. Broad tumor-associated expression and recognition by tumor-derived γδ T cells of MICA and MICB. Proc. Natl Acad. Sci. USA 96, 6879–6884 (1999).MICA and MICB are overexpressed on primary human tumours, providing targets for the immune system.
Bahram, S. MIC genes: from genetics to biology. Adv. Immunol. 76, 1–60 (2000).
Cosman, D. et al. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 14, 123–133 (2001).Identifies a viral glycoprotein encoded by human cytomegalovirus that binds to MICB and orthologues of the mouse RAE-1 antigens.
Nomura, M., Takihara, Y. & Shimada, K. Isolation and characterization of retinoic acid-inducible cDNA clones in F9 cells: one of the early inducible clones encodes a novel protein sharing several highly homologous regions with a Drosophila polyhomeotic protein. Differentiation 57, 39–50 (1994).
Malarkannan, S. et al. The molecular and functional characterization of a dominant minor H antigen, H60. J. Immunol. 161, 3501–3509 (1998).
Choi, E. Y. et al. Quantitative analysis of the immune response to mouse non-MHC transplantation antigens in vivo: the H60 histocompatibility antigen dominates over all others. J. Immunol. 166, 4370–4379 (2001).
Cerwenka, A. et al. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 12, 721–727 (2000).
Diefenbach, A., Jamieson, A. M., Liu, S. D., Shastri, N. & Raulet, D. H. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nature Immunol. 1, 119–126 (2000).References 36 and 37 show that the mouse NKG2D receptor binds to the RAE-1 family of proteins and the H60 minor histocompatibility antigen.
Lanier, L. L., Corliss, B. & Phillips, J. H. Arousal and inhibition of human NK cells. Immunol. Rev. 155, 145–154 (1997).
Biron, C. A., Byron, K. S. & Sullivan, J. L. Severe herpesvirus infections in an adolescent without natural killer cells. N. Engl. J. Med. 320, 1731–1735 (1989).
Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).
Tortorella, D., Gewurz, B. E., Furman, M. H., Schust, D. J. & Ploegh, H. L. Viral subversion of the immune system. Annu. Rev. Immunol. 18, 861–926 (2000).
Fletcher, J. M., Prentice, H. G. & Grundy, J. E. Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA. J. Immunol. 161, 2365–2374 (1998).
Leong, C. C. et al. Modulation of natural killer cell cytotoxicity in human cytomegalovirus infection: the role of endogenous class I MHC and a viral class I homolog. J. Exp. Med. 187, 1681–1687 (1998).
Siliciano, R. F., Pratt, J. C., Schmidt, R. E., Ritz, J. & Reinherz, E. L. Activation of cytolytic T lymphocyte and natural killer cell function through the T11 sheep erythrocyte binding protein. Nature 317, 428–430 (1985).
Schmidt, R. E., Bartley, G., Levine, H., Schlossman, S. F. & Ritz, J. Functional characterization of LFA-1 antigens in the interaction of human NK clones and targets. J. Immunol. 135, 1020–1025 (1985).
Timonen, T., Patarroyo, M. & Gahmberg, C. G. CD11a–c/CD18 and GP84 (LB-2) adhesion molecules on human large granular lymphocytes and their participation in natural killing. J. Immunol. 141, 1041–1046 (1988).
Huard, B. & Fruh, K. A role for MHC class I down-regulation in NK cell lysis of herpes virus-infected cells. Eur. J. Immunol. 30, 509–515 (2000).
Beck, S. & Barrell, B. G. Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I antigens. Nature 331, 269–272 (1988).
Fahnestock, M. L. et al. The MHC class I homolog encoded by human cytomegalovirus binds endogenous peptides. Immunity 3, 583–590 (1995).
Farrell, H. E. et al. Inhibition of natural killer cells by a cytomegalovirus MHC class I homologue in vivo. Nature 386, 510–514 (1997).
Cretney, E. et al. m144, a murine cytomegalovirus (MCMV)-encoded major histocompatibility complex class I homologue, confers tumor resistance to natural killer cell-mediated rejection. J. Exp. Med. 190, 435–444 (1999).
Cosman, D. et al. A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules. Immunity 7, 273–282 (1997).
Chapman, T. L. & Bjorkman, P. J. Characterization of a murine cytomegalovirus class I major histocompatibility complex (MHC) homolog: comparison to MHC molecules and to the human cytomegalovirus MHC homolog. J. Virol. 72, 460–466 (1998).
Chapman, T. L., Heikeman, A. P. & Bjorkman, P. J. The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11, 603–613 (1999).
Reyburn, H. T. et al. The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386, 514–517 (1997).
Soderberg-Naucler, C., Fish, K. N. & Nelson, J. A. Reactivation of latent human cytomegalovirus by allogeneic stimulation of blood cells from healthy donors. Cell 91, 119–126 (1997).
Hahn, G., Jores, R. & Mocarski, E. S. Cytomegalovirus remains latent in a common precursor of dendritic and myeloid cells. Proc. Natl Acad. Sci. USA 95, 3937–3942 (1998).
Tomasec, P. et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287, 1031–1033 (2000).Reports that the leader segment of human cytomegalovirus protein UL40 binds to human leukocyte antigen-E and protects cells from lysis by natural killer cells bearing the CD94/NKG2A inhibitory receptor.
Zhu, H., Cong, J. P., Mamtora, G., Gingeras, T. & Shenk, T. Cellular gene expression altered by human cytomegalovirus: global monitoring with oligonucleotide arrays. Proc. Natl Acad. Sci. USA 95, 14470–14475 (1998).
Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B, and C. Nature 391, 795–798 (1998).
Lee, N. et al. HLA-E is a major ligand for the NK inhibitory receptor CD94/NKG2A. Proc. Natl Acad. Sci. USA 95, 5199–5204 (1998).
Brooks, A. G. et al. Specific recognition of HLA-E, but not classical, HLA class I molecules by soluble CD94/NKG2A and NK cells. J. Immunol. 162, 305–313 (1999).
Braud, V., Jones, E. Y. & McMichael, A. The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur. J. Immunol. 27, 1164–1169 (1997).
Kaye, J., Browne, H., Stoffel, M. & Minson, T. The UL16 gene of human cytomegalovirus encodes a glycoprotein that is dispensable for growth in vitro. J. Virol. 66, 6609–6615 (1992).
Steinle, A. et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE1 protein family. Immunogenetics 53, 279–287 (2001).
Groh, V. et al. Costimulation of CD8αβ T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nature Immunol. 2, 255–260 (2001).MIC is induced by human cytomegalovirus-infected cells and this co-stimulates the effector functions of antigen-specific CD8+ cytotoxic T lymphocytes.
Bukowski, J. F., Warner, J. F., Dennert, G. & Welsh, R. M. Adoptive transfer studies demonstrating the antiviral effect of natural killer cells in vivo. J. Exp. Med. 161, 40–52 (1985).
Welsh, R. M., Burbaker, J. O., Vargas-Cortes, M. & O'Donnell, C. L. Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell functions. J. Exp. Med. 173, 1053–1063 (1991).
Scalzo, A. A., Fitzgerald, N. A., Simmons, A., La Vista, A. B. & Shellam, G. R. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J. Exp. Med. 171, 1469–1483 (1990).
Scalzo, A. A. et al. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J. Immunol. 149, 581–589 (1992).
Brown, M. G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).
Daniels, K. A. et al. Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J. Exp. Med. 194, 29–44 (2001).
Lee, H.-S. et al. Susceptibility to mouse cytomegalovirus is associated with depletion of an activating natural killer cell receptor of the C-type lectin superfamily. Nature Genet. 28, 42–45 (2001).References 71–73 implicate the activating Ly49H natural killer cell receptor in resistance to mouse cytomegalovirus.
Delano, M. L. & Brownstein, D. G. Innate resistance to lethal mousepox is genetically linked to the NK gene complex on chromosome 6 and correlates with early restriction of virus-replication by cells with an NK phenotype. J. Virol. 69, 5875–5877 (1995).
Pereira, R. A., Scalzo, A. & Simmons, A. Cutting edge: a NK complex-linked locus governs acute versus latent herpes simplex virus infection of neurons. J. Immunol. 166, 5869–5873 (2001).
Bakker, A. B. H. et al. DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13, 345–353 (2000).
Westgaard, I. H., Berg, S. F., Orstavik, S., Fossum, S. & Dissen, E. Identification of a human member of the Ly-49 multigene family. Eur. J. Immunol. 28, 1839–1846 (1998).
Barten, R. & Trowsdale, J. The human Ly-49L gene. Immunogenetics 49, 731–734 (1999).
Paloneva, J. et al. Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nature Genet. 25, 357–361 (2000).
Verloes, A. et al. Nasu–Hakola syndrome: polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy and presenile dementia. J. Med. Genet. 34, 753–757 (1997).
Cohen, G. B. et al. The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 10, 661–671 (1999).
Coscoy, L. & Ganem, D. Kaposi's sarcoma-associated herpesvirus encodes two proteins that block cell surface display of MHC class I chains by enhancing their endocytosis. Proc. Natl Acad. Sci. USA 97, 8051–8056 (2000).
Ishido, S., Wang, C., Lee, B. S., Cohen, G. B. & Jung, J. U. Downregulation of major histocompatibility complex class I molecules by Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins. J. Virol. 74, 5300–5309 (2000).
Coscoy, L. & Ganem, D. A viral protein that selectively downregulates ICAM-1 and B7-2 and modulates T cell costimulation. J. Clin. Invest. 107, 1599–1606 (2001).
Ishido, S. et al. Inhibition of natural killer cell-mediated cytotoxicity by Kaposi's sarcoma-associated herpesvirus K5 protein. Immunity 13, 365–374 (2000).
Garni-Wagner, B. A., Purohit, A., Mathew, P. A., Bennett, M. & Kumar, K. A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells. J. Immunol. 151, 60–70 (1993).
Nakajima, H., Cella, M., Langen, H., Friedlein, A. & Colonna, M. Activating interactions in human NK cell recognition: the role of 2B4-CD48. Eur. J. Immunol. 29, 1676–1683 (1999).
Tangye, S. G. et al. Human 2B4, an activating NK cell receptor, recruits the protein tyrosine phosphatase SHP-2 and the adaptor signaling protein SAP. J. Immunol. 162, 6981–6985 (1999).
Boles, K. S. et al. Molecular characterization of a novel human natural killer cell receptor homologous to mouse 2B4. Tissue Antigens 54, 27–34 (1999).
Sivori, S. et al. 2B4 functions as a co-receptor in human NK cell activation. Eur. J. Immunol. 30, 787–793 (2000).
Brown, M. H. et al. 2B4, the natural killer and T cell immunoglobulin superfamily surface protein, is a ligand for CD48. J. Exp. Med. 188, 2083–2090 (1998).
Latchman, Y., McKay, P. F. & Reiser, H. Identification of the 2B4 molecule as a counter-receptor for CD48. J. Immunol. 161, 5809–5812 (1998).
Kubin, M. Z. et al. Molecular cloning and biological characterization of NK cell activation-inducing ligand, a counterstructure for CD48. Eur. J. Immunol. 29, 3466–3477 (1999).
Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).
Tangye, S. G., Phillips, J. H., Lanier, L. L. & Nichols, K. E. Cutting edge: functional requirement for SAP in 2B4-mediated activation of human natural killer cells as revealed by the X-linked lymphoproliferative syndrome. J. Immunol. 165, 2932–2936 (2000).
Benoit, L., Wang, X., Pabst, H. F., Dutz, J. & Tan, R. Defective NK cell activation in X-linked lymphoproliferative disease. J. Immunol. 165, 3549–3553 (2000).
Nakajima, H. et al. Patients with X-linked lymphoproliferative disease have a defect in 2B4 receptor-mediated NK cell cytotoxicity. Eur. J. Immunol. 30, 3309–3318 (2000).
Parolini, S. et al. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J. Exp. Med. 192, 337–346 (2000).
Sayos, J. et al. Cell surface receptors Ly-9 and CD84 recruit the X-linked lymphoproliferative disease gene product SAP. Blood 97, 3867–3874 (2001).
Bottino, C. et al. NTB-A, a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. J. Exp. Med. 194, 235–246 (2001).
Cerwenka, A., Baron, J. L. & Lanier, L. L. Ectopic expression of RAE-1 permits NK cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc. Natl Acad. Sci. USA (in the press).
Pende, D. et al. Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin. Eur. J. Immunol. 31, 1076–1086 (2001).
Acknowledgements
This work was supported by grants from the National Institutes of Health. We thank R. Welsh, W. Yokoyama, S. Bahram and R. Strong for helpful discussions and sharing unpublished manuscripts.
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X-linked lymphoproliferative syndrome
FURTHER INFORMATION
Official List of Human MIC and HLA Antigens
Glossary
- NATURAL KILLER T CELLS
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(NKT cells). A subset of T lymphocytes expressing both NK and T-cell markers. In mice, NKT cells were first identified by their expression of the NK1.1 (NKR-P1C) alloantigen. Some mouse NKT cells express an invariant T-cell receptor (TCR) using the Vα14 variable region of the TCR-α chain and recognize CD1d-associated antigen. Similarly, human NKT cells express an invariant Vα24 receptor. NKT cells are characterized functionally by cytolytic activity and rapid production of cytokines, including IFN-γ and IL-4.
- γδ-TCR+ T CELLS
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T lymphocytes express either a T-cell receptor (TCR) composed of either α- and β-subunits (αβ-TCR) or a TCR composed of γ- and δ-subunits (γδ-TCR). Most (>90%) T cells have a αβ-TCR that recognizes conventional MHC class I or II ligands. T cells expressing γδ-TCR are less frequent and the ligands of this type of receptor are less well characterized.
- UL16-BINDING PROTEINS
-
(ULBP). A family of human glycoproteins with homology to MHC class I that was discovered by their ability to bind to UL16, a protein encoded by human cytomegalovirus. The ULBP proteins also serve as ligands for the NKG2D receptor. The mouse orthologues of the ULBP molecules are the retinoic acid early inducible 1 (RAE-1) genes.
- ORTHOLOGUES
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Homologous genes in different species, the lineages of which derive from a common ancestral gene without gene duplication or horizontal transmission.
- MICROARRAY ANALYSIS
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A technique for measuring the transcription of genes. It involves hybridization of fluorescent-labelled cDNA prepared from a cell or tissue of interest with glass slides or other surfaces dotted with thousands of oligonucleotides or cDNA, ideally representing all expressed genes in the species.
- NASU–HAKOLA DISEASE
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Also known as PLOSL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), it is a recessively inherited disease characterized by a unique combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. It is caused by a loss-of-function mutation in the DAP12 (Tyrobp) gene.
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Cerwenka, A., Lanier, L. Natural killer cells, viruses and cancer. Nat Rev Immunol 1, 41–49 (2001). https://doi.org/10.1038/35095564
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DOI: https://doi.org/10.1038/35095564
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