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The human CD94 gene encodes multiple, expressible transcripts including a new partner of NKG2A/B

Genes & Immunity volume 7, pages 36–43 (2006)Cite this article

Abstract

CD94/NKG2A is an inhibitory receptor expressed by natural killer (NK) cells and a subset of CD8+ T cells. Ligation of CD94/NKG2A by its ligand HLA-E results in tyrosine phosphorylation of the NKG2A immunoreceptor tyrosine-based inhibitory motifs, and recruitment and activation of the SH2 domain-bearing tyrosine phosphatase-1, which in turn suppresses activation signals. The nkg2a gene encodes two isoforms, NKG2A and NKG2B, with the latter lacking the stem region. We identified three new alternative transcripts of the cd94 gene in addition to the originally described canonical CD94Full. One of the transcripts, termed CD94-T4, lacks the portion that encodes the stem region. CD94-T4 associates with both NKG2A and NKG2B, but preferentially associates with the latter. This is probably due to the absence of a stem region in both CD94-T4 and NKG2B. 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. Coevolution of stemless isoforms of CD94 and NKG2A that preferentially pair with each other to produce a functional heterodimer indicates that this may be more than a serendipitous event. CD94-T4/NKG2B may contribute to the plasticity of the NK immunological synapse by insuring an adequate inhibitory signal.

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References

  1. Biron CA, Brossay L . NK cells and NKT cells in innate defense against viral infections. Curr Opin Immunol 2001; 13: 458–464.

    Article  CAS  Google Scholar 

  2. Soloski MJ . Recognition of tumor cells by the innate immune system. Curr Opin Immunol 2001; 13: 154–162.

    Article  CAS  Google Scholar 

  3. Lanier LL . NK cell recognition. Annu Rev Immunol 2005; 23: 225–274.

    Article  CAS  Google Scholar 

  4. Colucci F, Di Santo JP, Leibson PJ . Natural killer cell activation in mice and men: different triggers for similar weapons? Nat Immunol 2002; 3: 807–813.

    Article  CAS  Google Scholar 

  5. Moretta A, Bottino C, Vitale M, Pende D, Cantoni C, Mingari MC et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol 2001; 19: 197–223.

    Article  CAS  Google Scholar 

  6. Borrego F, Kabat J, Kim DK, Lieto L, Maasho K, Pena J et al. Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. Mol Immunol 2002; 38: 637–660.

    Article  CAS  Google Scholar 

  7. Kumar V, McNerney ME . A new self: MHC-class-I-independent natural-killer-cell self-tolerance. Nat Rev Immunol 2005; 5: 363–374.

    Article  CAS  Google Scholar 

  8. Lanier LL . Face off – the interplay between activating and inhibitory immune receptors. Curr Opin Immunol 2001; 13: 326–331.

    Article  CAS  Google Scholar 

  9. Kabat J, Borrego F, Brooks A, Coligan JE . Role that each NKG2A immunoreceptor tyrosine-based inhibitory motif plays in mediating the human CD94/NKG2A inhibitory signal. J Immunol 2002; 169: 1948–1958.

    Article  CAS  Google Scholar 

  10. Long EO . Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 1999; 17: 875–904.

    Article  CAS  Google Scholar 

  11. Brooks AG, Posch PE, Scorzelli CJ, Borrego F, Coligan JE . NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J Exp Med 1997; 185: 795–800.

    Article  CAS  Google Scholar 

  12. Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG . 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. J Exp Med 1998; 187: 813–818.

    Article  CAS  Google Scholar 

  13. Braud VM, Allan DS, O’Callaghan CA, Soderstrom K, D’Andrea A, Ogg GS et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 1998; 391: 795–799.

    Article  CAS  Google Scholar 

  14. Brooks AG, Borrego F, Posch PE, Patamawenu A, Scorzelli CJ, Ulbrecht M et al. Specific recognition of HLA-E, but not classical, HLA class I molecules by soluble CD94/NKG2A and NK cells. J Immunol 1999; 162: 305–313.

    CAS  PubMed  Google Scholar 

  15. Borrego F, Kabat J, Sanni TB, Coligan JE . NK cell CD94/NKG2A inhibitory receptors are internalized and recycle independently of inhibitory signaling processes. J Immunol 2002; 169: 6102–6111.

    Article  CAS  Google Scholar 

  16. Borrego F, Masilamani M, Kabat J, Sanni TB, Coligan JE . The cell biology of the human natural killer cell CD94/NKG2A inhibitory receptor. Mol Immunol 2005; 42: 485–488.

    Article  CAS  Google Scholar 

  17. Lieto LD, Borrego F, You CH, Coligan JE . Human CD94 gene expression: dual promoters differing in responsiveness to IL-2 or IL-15. J Immunol 2003; 171: 5277–5286.

    Article  CAS  Google Scholar 

  18. Marusina AI, Kim DK, Lieto LD, Borrego F, Coligan JE . GATA-3 is an important transcription factor for regulating human NKG2A gene expression. J Immunol 2005; 174: 2152–2159.

    Article  CAS  Google Scholar 

  19. Bellon T, Heredia AB, Llano M, Minguela A, Rodriguez A, Lopez-Botet M et al. Triggering of effector functions on a CD8+ T cell clone upon the aggregation of an activatory CD94/kp39 heterodimer. J Immunol 1999; 162: 3996–4002.

    CAS  PubMed  Google Scholar 

  20. Plougastel B, Jones T, Trowsdale J . Genomic structure, chromosome location, and alternative splicing of the human NKG2A gene. Immunogenetics 1996; 44: 286–291.

    Article  CAS  Google Scholar 

  21. Furukawa H, Yabe T, Watanabe K, Miyamoto R, Akaza T, Tadokoro K et al. An alternatively spliced form of the human CD94 gene. Immunogenetics 1998; 48: 87–88.

    Article  CAS  Google Scholar 

  22. Chang C, Rodriguez A, Carretero M, Lopez-Botet M, Phillips JH, Lanier LL . Molecular characterization of human CD94: a type II membrane glycoprotein related to the C-type lectin superfamily. Eur J Immunol 1995; 25: 2433–2437.

    Article  CAS  Google Scholar 

  23. Boyington JC, Raiz AN, Brooks AG, Patamawenu A, Sun PD . Reconstitution of bacterial expressed human CD94: the importance of the stem region for dimer formation. Protein Exp Purif 2000; 18: 235–241.

    Article  CAS  Google Scholar 

  24. Boyington JC, Riaz AN, Patamawenu A, Coligan JE, Brooks AG, Sun PD . Structure of CD94 reveals a novel C-type lectin fold: implications for the NK cell-associated CD94/NKG2 receptors. Immunity 1999; 10: 75–82.

    Article  CAS  Google Scholar 

  25. Phillips JH, Chang C, Mattson J, Gumperz JE, Parham P, Lanier LL . CD94 and a novel associated protein (94AP) form a NK cell receptor involved in the recognition of HLA-A, HLA-B, and HLA-C allotypes. Immunity 1996; 5: 163–172.

    Article  CAS  Google Scholar 

  26. McCann FE, Suhling K, Carlin LM, Eleme K, Taner SB, Yanagi K et al. Imaging immune surveillance by T cells and NK cells. Immunol Rev 2002; 189: 179–192.

    Article  CAS  Google Scholar 

  27. Vyas YM, Maniar H, Dupont B . Visualization of signaling pathways and cortical cytoskeleton in cytolytic and noncytolytic natural killer cell immune synapses. Immunol Rev 2002; 189: 161–178.

    Article  CAS  Google Scholar 

  28. Vyas YM, Mehta KM, Morgan M, Maniar H, Butros L, Jung S et al. Spatial organization of signal transduction molecules in the NK cell immune synapses during MHC class I-regulated noncytolytic and cytolytic interactions. J Immunol 2001; 167: 4358–4367.

    Article  CAS  Google Scholar 

  29. Fassett MS, Davis DM, Valter MM, Cohen GB, Strominger JL . Signaling at the inhibitory natural killer cell immune synapse regulates lipid raft polarization but not class I MHC clustering. Proc Natl Acad Sci USA 2001; 98: 14547–14552.

    Article  CAS  Google Scholar 

  30. Sanni TB, Masilamani M, Kabat J, Coligan JE, Borrego F . Exclusion of lipid rafts and decreased mobility of CD94/NKG2A receptors at the inhibitory NK cell synapse. Mol Biol Cell 2004; 15: 3210–3223.

    Article  CAS  Google Scholar 

  31. McCann FE, Vanherberghen B, Eleme K, Carlin LM, Newsam RJ, Goulding D et al. The size of the synaptic cleft and distinct distributions of filamentous actin, ezrin, CD43, and CD45 at activating and inhibitory human NK cell immune synapses. J Immunol 2003; 170: 2862–2870.

    Article  CAS  Google Scholar 

  32. Burroughs NJ, Wulfing C . Differential segregation in a cell-cell contact interface: the dynamics of the immunological synapse. Biophys J 2002; 83: 1784–1796.

    Article  CAS  Google Scholar 

  33. Davis DM, Chiu I, Fassett M, Cohen GB, Mandelboim O, Strominger JL . The human natural killer cell immune synapse. Proc Natl Acad Sci USA 1999; 96: 15062–15067.

    Article  CAS  Google Scholar 

  34. Choudhuri K, Wiseman D, Brown MH, Gould K, van der Merwe PA . T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 2005; 436: 578–582.

    Article  CAS  Google Scholar 

  35. Davis SJ, Ikemizu S, Evans EJ, Fugger L, Bakker TR, van der Merwe PA . The nature of molecular recognition by T cells. Nat Immunol 2003; 4: 217–224.

    Article  CAS  Google Scholar 

  36. Vales-Gomez M, Reyburn HT, Erskine RA, Lopez-Botet M, Strominger JL . 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. Embo J 1999; 18: 4250–4260.

    Article  CAS  Google Scholar 

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Acknowledgements

We appreciate the advice and comments of Drs Steven Burgess, Madhan Masilamani, Sriram Narayanan and Xiaobin Tang. We also would like to thank Robert Valas for the NK cell isolation. This work was supported by the NIAID, National Institutes of Health Intramural Research Program.

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Author notes

  1. L D Lieto

    Present address: US Patent and Trademark Office, 400 Dulany Street, Alexandria, VA, 22314, USA

  2. D West

    Present address: University of Louisville School of Medicine, Louisville, Kentucky, 40202, USA

Authors and Affiliations

  1. Receptor Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    L D Lieto, K Maasho, D West, F Borrego & J E Coligan

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  1. L D Lieto
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Correspondence to J E Coligan.

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Lieto, L., Maasho, K., West, D. et al. The human CD94 gene encodes multiple, expressible transcripts including a new partner of NKG2A/B. Genes Immun 7, 36–43 (2006). https://doi.org/10.1038/sj.gene.6364268

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  • DOI: https://doi.org/10.1038/sj.gene.6364268

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