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The NKG2D receptor: immunobiology and clinical implications

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Abstract

NK cells are critical components of our immune system functioning, in part, to recognize and then eradicate virally infected or tumorigenic cells without previous sensitization. One of the best-characterized activating receptors expressed on NK cells is the NKG2D receptor, which is capable of transmitting co-stimulatory signals by subsets of T cells. Viruses and tumors have evolved strategies to evade NKG2D-mediated immune recognition thus highlighting the importance of this receptor in immunity. This review will focus on the structure of NKG2D and its interaction with its diverse array of ligands, as well as highlighting current knowledge regarding NKG2D signal transduction and biological mechanisms that govern its cell surface expression. The impact that NKG2D has in disease pathologies is also assessed.

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References

  1. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003;3:781–790

    PubMed  CAS  Google Scholar 

  2. Lazetic S, Chang C, Houchins JP, Lanier LL, Phillips JH. Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. J Immunol 1996;157:4741–4745

    PubMed  CAS  Google Scholar 

  3. Gilfillan S, Ho EL, Cella M, Yokoyama WM, Colonna M. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat Immunol 2002;3:1150–1155

    PubMed  CAS  Google Scholar 

  4. Wu J, Song Y, Bakker AB, Bauer S, Spies T, Lanier LL, Phillips JH. An activating immunoreceptor complex formed by NKG2D and DAP10. Science 1999;285:730–732

    PubMed  CAS  Google Scholar 

  5. Rosen DB, Araki M, Hamerman JA, Chen T, Yamamura T, Lanier LL. A Structural basis for the association of DAP12 with mouse, but not human, NKG2D. J Immunol 2004;173:2470–2478

    PubMed  CAS  Google Scholar 

  6. Upshaw JL, Arneson LN, Schoon RA, Dick CJ, Billadeau DD, Leibson PJ. NKG2D-mediated signaling requires a DAP10-bound Grb2-Vav1 intermediate and phosphatidylinositol-3-kinase in human natural killer cells. Nat Immunol 2006;7:524–532

    PubMed  CAS  Google Scholar 

  7. Diefenbach A, Tomasello E, Lucas M, Jamieson AM, Hsia JK, Vivier E, Raulet DH. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat Immunol 2002;3:1142–1149

    PubMed  CAS  Google Scholar 

  8. Garrity D, Call ME, Feng J, Wucherpfennig KW. The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. Proc Natl Acad Sci U S A 2005;102:7641–7646

    PubMed  CAS  Google Scholar 

  9. Wolan DW, Teyton L, Rudolph MG, Villmow B, Bauer S, Busch DH, Wilson IA. Crystal structure of the murine NK cell-activating receptor NKG2D at 1.95 A. Nat Immunol 2001;2:248–254

    PubMed  CAS  Google Scholar 

  10. Li P, Morris DL, Willcox BE, Steinle A, Spies T, Strong RK. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nat Immunol 2001;2:443–451

    PubMed  CAS  Google Scholar 

  11. Radaev S, Rostro B, Brooks AG, Colonna M, Sun PD. Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3. Immunity 2001;15:1039–1049

    PubMed  CAS  Google Scholar 

  12. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999;285:727–729

    PubMed  CAS  Google Scholar 

  13. Bahram S, Mizuki N, Inoko H, Spies T. Nucleotide sequence of the human MHC class I MICA gene. Immunogenetics 1996;44:80–81

    PubMed  CAS  Google Scholar 

  14. Bahram S. MIC genes: from genetics to biology. Adv Immunol 2000;76:1–60

    PubMed  CAS  Google Scholar 

  15. Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A 1996;93:12445–12450

    PubMed  CAS  Google Scholar 

  16. Perez-Rodriguez M, Arguello JR, Fischer G, Corell A, Cox ST, Robinson J, Hossain E, McWhinnie A, Travers PJ, Marsh SG, Madrigal JA. Further polymorphism of the MICA gene. Eur J Immunogenet 2002;29:35–46

    PubMed  CAS  Google Scholar 

  17. Hughes EH, Collins RW, Kondeatis E, Wallace GR, Graham EM, Vaughan RW, Stanford MR. Associations of major histocompatibility complex class I chain-related molecule polymorphisms with Behcet’s disease in Caucasian patients. Tissue Antigens 2005;66:195–199

    PubMed  CAS  Google Scholar 

  18. Martinez-Borra J, Gonzalez S, Lopez-Vazquez A, Gelaz MA, Armas JB, Kanga U, Mehra NK, Lopez-Larrea C. HLA-B27 alone rather than B27-related class I haplotypes contributes to ankylosing spondylitis susceptibility. Hum Immunol 2000;61:131–139

    PubMed  CAS  Google Scholar 

  19. Gonzalez S, Brautbar C, Martinez-Borra J, Lopez-Vazquez A, Segal R, Blanco-Gelaz MA, Enk CD, Safriman C, Lopez-Larrea C. Polymorphism in MICA rather than HLA-B/C genes is associated with psoriatic arthritis in the Jewish population. Hum Immunol 2001;62:632–638

    PubMed  CAS  Google Scholar 

  20. Gonzalez S, Martinez-Borra J, Lopez-Vazquez A, Garcia-Fernandez S, Torre-Alonso JC, Lopez-Larrea C. MICA rather than MICB, TNFA, or HLA-DRB1 is associated with susceptibility to psoriatic arthritis. J Rheumatol 2002;29:973–978

    PubMed  CAS  Google Scholar 

  21. Huang Y, Lee YJ, Chen MR, Hsu CH, Lin SP, Sung TC, Chang SC, Chang JG. Polymorphism of transmembrane region of MICA gene and Kawasaki disease. Exp Clin Immunogenet 2000;17:130–137

    PubMed  CAS  Google Scholar 

  22. Cosman D, Mullberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ. ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity 2001;14:123–133

    PubMed  CAS  Google Scholar 

  23. Kubin M, Cassiano L, Chalupny J, Chin W, Cosman D, Fanslow W, Mullberg J, Rousseau AM, Ulrich D, Armitage R. ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells. Eur J Immunol 2001;31:1428–1437

    PubMed  CAS  Google Scholar 

  24. Jan Chalupny N, Sutherland CL, Lawrence WA, Rein-Weston A, Cosman D. ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun 2003;305:129–135

    PubMed  CAS  Google Scholar 

  25. Diefenbach A, Jensen ER, Jamieson AM, Raulet DH. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 2001;413:165–171

    PubMed  CAS  Google Scholar 

  26. Zou Z, Nomura M, Takihara Y, Yasunaga T, Shimada K. Isolation and characterization of retinoic acid-inducible cDNA clones in F9 cells: a novel cDNA family encodes cell surface proteins sharing partial homology with MHC class I molecules. J Biochem (Tokyo) 1996;119:319–328

    CAS  Google Scholar 

  27. Cerwenka A, Bakker AB, McClanahan T, Wagner J, Wu J, Phillips JH, Lanier LL. Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity 2000;12:721–727

    PubMed  CAS  Google Scholar 

  28. Carayannopoulos LN, Naidenko OV, Fremont DH, Yokoyama WM. Cutting edge: murine UL16-binding protein-like transcript 1: a newly described transcript encoding a high-affinity ligand for murine NKG2D. J Immunol 2002;169:4079–4083

    PubMed  CAS  Google Scholar 

  29. O’Callaghan CA, Cerwenka A, Willcox BE, Lanier LL, Bjorkman PJ. Molecular competition for NKG2D: H60 and RAE1 compete unequally for NKG2D with dominance of H60. Immunity 2001;15:201–211

    PubMed  CAS  Google Scholar 

  30. Strong RK. Asymmetric ligand recognition by the activating natural killer cell receptor NKG2D, a symmetric homodimer. Mol Immunol 2002;38:1029–1037

    PubMed  CAS  Google Scholar 

  31. Steinle A, Li P, Morris DL, Groh V, Lanier LL, Strong RK, Spies T. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics 2001;53:279–287

    PubMed  CAS  Google Scholar 

  32. Radaev S, Sun PD. Structure and function of natural killer cell surface receptors. Annu Rev Biophys Biomol Struct 2003;32:93–114

    PubMed  CAS  Google Scholar 

  33. Groh V, Steinle A, Bauer S, Spies T. Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science 1998;279:1737–1740

    PubMed  CAS  Google Scholar 

  34. Steinle A, Groh V, Spies T. Diversification, expression, and gamma delta T cell recognition of evolutionarily distant members of the MIC family of major histocompatibility complex class I-related molecules. Proc Natl Acad Sci U S A 1998;95:12510–12515

    PubMed  CAS  Google Scholar 

  35. McFarland BJ, Kortemme T, Yu SF, Baker D, Strong RK. Symmetry recognizing asymmetry: analysis of the interactions between the C-type lectin-like immunoreceptor NKG2D and MHC class I-like ligands. Structure 2003;11:411–422

    PubMed  CAS  Google Scholar 

  36. Billadeau DD, Upshaw JL, Schoon RA, Dick CJ, Leibson PJ. NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. Nat Immunol 2003;4:557–564

    PubMed  CAS  Google Scholar 

  37. Ward SG. CD28: a signalling perspective. Biochem J 1996;318(Pt 2):361–377

    PubMed  CAS  Google Scholar 

  38. Hornstein I, Alcover A, Katzav S. Vav proteins, masters of the world of cytoskeleton organization. Cell Signal 2004;16:1–11

    PubMed  CAS  Google Scholar 

  39. Bustelo XR. Vav proteins, adaptors and cell signaling. Oncogene 2001;20:6372–6381

    PubMed  CAS  Google Scholar 

  40. Sutherland CL, Chalupny NJ, Schooley K, VandenBos T, Kubin M, Cosman D. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells. J Immunol 2002;168:671–679

    PubMed  CAS  Google Scholar 

  41. Cantrell D. Protein kinase B (Akt) regulation and function in T lymphocytes. Semin Immunol 2002;14:19–26

    PubMed  CAS  Google Scholar 

  42. Cella M, Fujikawa K, Tassi I, Kim S, Latinis K, Nishi S, Yokoyama W, Colonna M, Swat W. Differential requirements for Vav proteins in DAP10- and ITAM-mediated NK cell cytotoxicity. J Exp Med 2004;200:817–823

    PubMed  CAS  Google Scholar 

  43. Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B. Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 2004;21:357–366

    PubMed  CAS  Google Scholar 

  44. Andre P, Castriconi R, Espeli M, Anfossi N, Juarez T, Hue S, Conway H, Romagne F, Dondero A, Nanni M, Caillat-Zucman S, Raulet DH, Bottino C, Vivier E, Moretta A, Paul P. Comparative analysis of human NK cell activation induced by NKG2D and natural cytotoxicity receptors. Eur J Immunol 2004;34:961–971

    PubMed  CAS  Google Scholar 

  45. Bryceson YT, March ME, Ljunggren HG, Long EO. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 2006;7:159–166

    Google Scholar 

  46. Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH. The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 2002;17:19–29

    PubMed  CAS  Google Scholar 

  47. Zompi S, Hamerman JA, Ogasawara K, Schweighoffer E, Tybulewicz VL, Di Santo JP, Lanier LL, Colucci F. NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases. Nat Immunol 2003;4:565–572

    PubMed  CAS  Google Scholar 

  48. Diefenbach A, Jamieson AM, Liu SD, Shastri N, Raulet DH. Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol 2000;1:119–126

    PubMed  CAS  Google Scholar 

  49. Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T. Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol 2001;2:255–260

    PubMed  CAS  Google Scholar 

  50. Maasho K, Opoku-Anane J, Marusina AI, Coligan JE, Borrego F. NKG2D is a costimulatory receptor for human naive CD8+ T cells. J Immunol 2005;174:4480–4484

    PubMed  CAS  Google Scholar 

  51. Regunathan J, Chen Y, Wang D, Malarkannan S. NKG2D receptor-mediated NK cell function is regulated by inhibitory Ly49 receptors. Blood 2005;105:233–240

    PubMed  CAS  Google Scholar 

  52. Masilamani M, Nguyen C, Kabat J, Borrego F, Coligan JE. CD94/NKG2A inhibits NK cell activation by disrupting the actin network at the immunological synapse. J Immunol 2006;177:3590–3596

    PubMed  CAS  Google Scholar 

  53. Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo. Proc Natl Acad Sci U S A 2001;98:11521–11526

    PubMed  CAS  Google Scholar 

  54. Moretta L, Moretta A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. Embo J 2004;23:255–259

    PubMed  CAS  Google Scholar 

  55. Gonzalez S, Groh V, Spies T. Immunobiology of human NKG2D and its ligands. Curr Top Microbiol Immunol 2006;298:121–138

    Article  PubMed  CAS  Google Scholar 

  56. Houchins JP, Yabe T, McSherry C, Bach FH. 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 1991;173:1017–1020

    PubMed  CAS  Google Scholar 

  57. Plougastel B, Trowsdale J. Cloning of NKG2-F, a new member of the NKG2 family of human natural killer cell receptor genes. Eur J Immunol 1997;27:2835–2839

    PubMed  CAS  Google Scholar 

  58. 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

    PubMed  CAS  Google Scholar 

  59. 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

    PubMed  CAS  Google Scholar 

  60. Yim D, Jie HB, Sotiriadis J, Kim YS, Kim KS, Rothschild MF, Lanier LL, Kim YB. Molecular cloning and characterization of pig immunoreceptor DAP10 and NKG2D. Immunogenetics 2001;53:243–249

    PubMed  CAS  Google Scholar 

  61. Dhanji S, Teh HS. IL-2-activated CD8+CD44high cells express both adaptive and innate immune system receptors and demonstrate specificity for syngeneic tumor cells. J Immunol 2003;171:3442–3450

    PubMed  CAS  Google Scholar 

  62. Verneris MR, Karami M, Baker J, Jayaswal A, Negrin RS. Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells. Blood 2004;103:3065–3072

    PubMed  CAS  Google Scholar 

  63. Dann SM, Wang HC, Gambarin KJ, Actor JK, Robinson P, Lewis DE, Caillat-Zucman S, White AC Jr. Interleukin-15 activates human natural killer cells to clear the intestinal protozoan cryptosporidium. J Infect Dis 2005;192:1294–1302

    PubMed  CAS  Google Scholar 

  64. Roberts AI, Lee L, Schwarz E, Groh V, Spies T, Ebert EC, Jabri B. NKG2D receptors induced by IL-15 costimulate CD28-negative effector CTL in the tissue microenvironment. J Immunol 2001;167:5527–5530

    PubMed  CAS  Google Scholar 

  65. Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci U S A 2003;100:9452–9457

    PubMed  CAS  Google Scholar 

  66. Takaki R, Hayakawa Y, Nelson A, Sivakumar PV, Hughes S, Smyth MJ, Lanier LL. IL-21 enhances tumor rejection through a NKG2D-dependent mechanism. J Immunol 2005;175:2167–2173

    PubMed  CAS  Google Scholar 

  67. Burgess SJ, Marusina AI, Pathmanathan I, Borrego F, Coligan JE. IL-21 down-regulates NKG2D/DAP10 expression on human NK and CD8+ T cells. J Immunol 2006;176:1490–1497

    PubMed  CAS  Google Scholar 

  68. Chiesa MD, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, Moretta L, Moretta A, Vitale M. The tryptophan catabolite l-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood 2006;108:4118–4125

    PubMed  Google Scholar 

  69. Zhang C, Tian ZG, Zhang J, Feng JB, Zhang JH, Xu XQ. The negative regulatory effect of IFN-gamma on cognitive function of human natural killer cells. Zhonghua Zhong Liu Za Zhi 2004;26:324–327

    PubMed  CAS  Google Scholar 

  70. Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A. Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci U S A 2003;100:4120–4125

    PubMed  CAS  Google Scholar 

  71. Lee JC, Lee KM, Kim DW, Heo DS. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 2004;172:7335–7340

    PubMed  CAS  Google Scholar 

  72. Dasgupta S, Bhattacharya-Chatterjee M, O’Malley BW Jr., Chatterjee SK. Inhibition of NK cell activity through TGF-{beta}1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol 2005;175:5541–5550

    PubMed  CAS  Google Scholar 

  73. Ghiringhelli F, Menard C, Terme M, Flament C, Taieb J, Chaput N, Puig PE, Novault S, Escudier B, Vivier E, Lecesne A, Robert C, Blay JY, Bernard J, Caillat-Zucman S, Freitas A, Tursz T, Wagner-Ballon O, Capron C, Vainchencker W, Martin F, Zitvogel L. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J Exp Med 2005;202:1075–1085

    PubMed  CAS  Google Scholar 

  74. Friese MA, Wischhusen J, Wick W, Weiler M, Eisele G, Steinle A, Weller M. RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Res 2004;64:7596–7603

    PubMed  CAS  Google Scholar 

  75. Song H, Hur DY, Kim KE, Park H, Kim T, Kim CW, Bang S, Cho DH. IL-2/IL-18 prevent the down-modulation of NKG2D by TGF-beta in NK cells via the c-Jun N-terminal kinase (JNK) pathway. Cell Immunol 2006;242:39–45

    PubMed  CAS  Google Scholar 

  76. Groh V, Wu J, Yee C, Spies T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 2002;419:734–738

    PubMed  CAS  Google Scholar 

  77. Raffaghello L, Prigione I, Airoldi I, Camoriano M, Levreri I, Gambini C, Pende D, Steinle A, Ferrone S, Pistoia V. Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Neoplasia 2004;6:558–568

    PubMed  CAS  Google Scholar 

  78. Holdenrieder S, Stieber P, Peterfi A, Nagel D, Steinle A, Salih HR. Soluble MICA in malignant diseases. Int J Cancer 2006;118:684–687

    Google Scholar 

  79. Salih HR, Rammensee HG, Steinle A. Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 2002;169:4098–4102

    PubMed  CAS  Google Scholar 

  80. Groh V, Smythe K, Dai Z, Spies T. Fas ligand-mediated paracrine T cell regulation by the receptor NKG2D in tumor immunity. Nat Immunol 2006;7:755–762

    PubMed  CAS  Google Scholar 

  81. Mincheva-Nilsson L, Nagaeva O, Chen T, Stendahl U, Antsiferova J, Mogren I, Hernestal J, Baranov V. Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival. J Immunol 2006;176:3585–3592

    PubMed  CAS  Google Scholar 

  82. Oppenheim DE, Roberts SJ, Clarke SL, Filler R, Lewis JM, Tigelaar RE, Girardi M, Hayday AC. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nat Immunol 2005;6:928–937

    PubMed  CAS  Google Scholar 

  83. Coudert JD, Zimmer J, Tomasello E, Cebecauer M, Colonna M, Vivier E, Held W. Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells. Blood 2005;106:1711–1717

    PubMed  CAS  Google Scholar 

  84. Hayakawa Y, Smyth MJ. Innate immune recognition and suppression of tumors. Adv Cancer Res 2006;95:293–322

    PubMed  CAS  Google Scholar 

  85. Salih HR, Antropius H, Gieseke F, Lutz SZ, Kanz L, Rammensee HG, Steinle A. Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia. Blood 2003;102:1389–1396

    PubMed  CAS  Google Scholar 

  86. Jinushi M, Hodi FS, Dranoff G. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc Natl Acad Sci U S A 2006;103:9190–9195

    PubMed  CAS  Google Scholar 

  87. Hue S, Mention JJ, Monteiro RC, Zhang S, Cellier C, Schmitz J, Verkarre V, Fodil N, Bahram S, Cerf-Bensussan N, Caillat-Zucman S. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 2004;21:367–377

    PubMed  Google Scholar 

  88. Stepniak D, Koning F. Celiac disease–sandwiched between innate and adaptive immunity. Hum Immunol 2006;67:460–468

    PubMed  CAS  Google Scholar 

  89. Senger S, Maurano F, Mazzeo MF, Gaita M, Fierro O, David CS, Troncone R, Auricchio S, Siciliano RA, Rossi M. Identification of immunodominant epitopes of alpha-gliadin in HLA-DQ8 transgenic mice following oral immunization. J Immunol 2005;175:8087–8095

    PubMed  CAS  Google Scholar 

  90. Martin-Pagola A, Ortiz L, Perez de Nanclares G, Vitoria JC, Castano L, Bilbao JR. Analysis of the expression of MICA in small intestinal mucosa of patients with celiac disease. J Clin Immunol 2003;23:498–503

    PubMed  CAS  Google Scholar 

  91. Caillat-Zucman S. How NKG2D ligands trigger autoimmunity? Hum Immunol 2006;67:204–207

    PubMed  CAS  Google Scholar 

  92. Goronzy JJ, Weyand CM. T-cell regulation in rheumatoid arthritis. Curr Opin Rheumatol 2004;16:212–217

    PubMed  CAS  Google Scholar 

  93. Ogasawara K, Hamerman JA, Ehrlich LR, Bour-Jordan H, Santamaria P, Bluestone JA, Lanier LL. NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 2004;20:757–767

    PubMed  CAS  Google Scholar 

  94. Wicker LS, Todd JA, Peterson LB. Genetic control of autoimmune diabetes in the NOD mouse. Annu Rev Immunol 1995;13:179–200

    PubMed  CAS  Google Scholar 

  95. Rogner UC, Boitard C, Morin J, Melanitou E, Avner P. Three loci on mouse chromosome 6 influence onset and final incidence of type I diabetes in NOD.C3H congenic strains. Genomics 2001;74:163–171

    PubMed  CAS  Google Scholar 

  96. Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol 2001;1:41–49

    PubMed  CAS  Google Scholar 

  97. Lenac T, Budt M, Arapovic J, Hasan M, Zimmermann A, Simic H, Krmpotic A, Messerle M, Ruzsics Z, Koszinowski UH, Hengel H, Jonjic S. The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60. J Exp Med 2006;203:1843–1850

    PubMed  CAS  Google Scholar 

  98. Dunn C, Chalupny NJ, Sutherland CL, Dosch S, Sivakumar PV, Johnson DC, Cosman D. Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration of NKG2D ligands, protecting against natural killer cell cytotoxicity. J Exp Med 2003;197:1427–1439

    PubMed  CAS  Google Scholar 

  99. Welte SA, Sinzger C, Lutz SZ, Singh-Jasuja H, Sampaio KL, Eknigk U, Rammensee HG, Steinle A. Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein. Eur J Immunol 2003;33:194–203

    PubMed  CAS  Google Scholar 

  100. Rolle A, Mousavi-Jazi M, Eriksson M, Odeberg J, Soderberg-Naucler C, Cosman D, Karre K, Cerboni C. Effects of human cytomegalovirus infection on ligands for the activating NKG2D receptor of NK cells: up-regulation of UL16-binding protein (ULBP)1 and ULBP2 is counteracted by the viral UL16 protein. J Immunol 2003;171:902–908

    PubMed  Google Scholar 

  101. Chalupny NJ, Rein-Weston A, Dosch S, Cosman D. Down-regulation of the NKG2D ligand MICA by the human cytomegalovirus glycoprotein UL142. Biochem Biophys Res Commun 2006;346:175–181

    PubMed  CAS  Google Scholar 

  102. Lodoen M, Ogasawara K, Hamerman JA, Arase H, Houchins JP, Mocarski ES, Lanier LL. NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules. J Exp Med 2003;197:1245–1253

    PubMed  CAS  Google Scholar 

  103. Krmpotic A, Busch DH, Bubic I, Gebhardt F, Hengel H, Hasan M, Scalzo AA, Koszinowski UH, Jonjic S. MCMV glycoprotein gp40 confers virus resistance to CD8+ T cells and NK cells in vivo. Nat Immunol 2002;3:529–535

    PubMed  CAS  Google Scholar 

  104. Hasan M, Krmpotic A, Ruzsics Z, Bubic I, Lenac T, Halenius A, Loewendorf A, Messerle M, Hengel H, Jonjic S, Koszinowski UH. Selective down-regulation of the NKG2D ligand H60 by mouse cytomegalovirus m155 glycoprotein. J Virol 2005;79:2920–2930

    PubMed  CAS  Google Scholar 

  105. Krmpotic A, Hasan M, Loewendorf A, Saulig T, Halenius A, Lenac T, Polic B, Bubic I, Kriegeskorte A, Pernjak-Pugel E, Messerle M, Hengel H, Busch DH, Koszinowski UH, Jonjic S. NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145. J Exp Med 2005;201:211–220

    PubMed  CAS  Google Scholar 

  106. Budt M, Reinhard H, Bigl A, Hengel H. Herpesviral Fcgamma receptors: culprits attenuating antiviral IgG? Int Immunopharmacol 2004;4:1135–1148

    PubMed  CAS  Google Scholar 

  107. Thale R, Lucin P, Schneider K, Eggers M, Koszinowski UH. Identification and expression of a murine cytomegalovirus early gene coding for an Fc receptor. J Virol 1994;68:7757–7765

    PubMed  CAS  Google Scholar 

  108. Collins RW. Human MHC class I chain related (MIC) genes: their biological function and relevance to disease and transplantation. Eur J Immunogenet 2004;31:105–114

    PubMed  CAS  Google Scholar 

  109. Mizutani K, Terasaki P, Bignon JD, Hourmant M, Cesbron-Gautier A, Shih RN, Pei R, Lee J, Ozawa M. Association of kidney transplant failure and antibodies against MICA. Hum Immunol 2006;67:683–691

    PubMed  CAS  Google Scholar 

  110. Suarez-Alvarez B, Lopez-Vazquez A, Diaz-Molina B, Bernardo-Rodriguez MJ, Alvarez-Lopez R, Pascual D, Astudillo A, Martinez-Borra J, Lambert JL, Gonzalez S, Lopez-Larrea C. The predictive value of soluble major histocompatibility complex class I chain-related molecule A (MICA) levels on heart allograft rejection. Transplantation 2006;82:354–361

    PubMed  CAS  Google Scholar 

  111. Ogasawara K, Benjamin J, Takaki R, Phillips JH, Lanier LL. Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nat Immunol 2005;6:938–945

    PubMed  CAS  Google Scholar 

  112. Seiler M, Brabcova I, Viklicky O, Hribova P, Rosenberger C, Pratschke J, Lodererova A, Matz M, Schonemann C, Reinke P, Volk HD, Kotsch K. Heightened expression of the cytotoxicity receptor NKG2D correlates with acute and chronic nephropathy after kidney transplantation. Am J Transplant 2007;7(2):423–433

    Google Scholar 

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Correspondence to John E. Coligan.

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Burgess, S.J., Maasho, K., Masilamani, M. et al. The NKG2D receptor: immunobiology and clinical implications. Immunol Res 40, 18–34 (2008). https://doi.org/10.1007/s12026-007-0060-9

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  • DOI: https://doi.org/10.1007/s12026-007-0060-9

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