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Immunobiology of Human NKG2D and Its Ligands

  • Chapter
Immunobiology of Natural Killer Cell Receptors

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 298))

Abstract

The NKG2D-DAP10 receptor complex activates natural killer (NK) cells and costimulates effector T cell subsets upon engagement of ligands that can be conditionally expressed under physiologically harmful conditions such as microbial infections and malignancies. These characteristics have given rise to the widely embraced concept of immunorecognition of “induced or damaged self,” complementing the “missing self” paradigm that is represented by MHC class I allotypes and their interactions with inhibitory receptors on NK cells. However, this notion may only be partially sustainable, as various patterns of constitutive tissue distributions have become apparent among members of one NKG2D ligand family. This review summarizes the biological properties of NKG2D and its ligands and discusses the interactions and regulation of these molecules with emphasis of their significance in microbial infections, tumor immunology, and autoimmune disease.

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References

  • Bacon L, Eagle RA, Meyer M, Easom N, Young NT, Trowsdale J (2004) Two human ULBP/RAET1 molecules with transmembrane regions are ligands for NKG2D. J Immunol 173:1078–1084

    CAS  PubMed  Google Scholar 

  • Bahram S, Bresnahan M, Geraghty DE, Spies T (1994) A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci USA 91:6259–6263

    CAS  PubMed  Google Scholar 

  • Bahram S, Spies T (1996) Nucleotide sequence of a human MHC class I MICB cDNA. Immunogenetics 43:230–233

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Borges L, Hsu M-L, Fanger N, Kubin M, Cosman D (1997) A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J Immunol 159:5192–5196

    CAS  PubMed  Google Scholar 

  • Cantoni C, Bottino C, Vitale M, Pessino A, Augugliaro R, Malaspina A, Parolini S, Moretta L, Moretta A, Biassoni R (1999) 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

    Article  CAS  PubMed  Google Scholar 

  • Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A (2003) Transforming growth factor β1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci USA 100:4120–4125

    Article  CAS  PubMed  Google Scholar 

  • Cerwenka A, Baron JL, Lanier LL (2001) 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 USA 98: 11521–11526

    Article  CAS  PubMed  Google Scholar 

  • Chalupny NJ, Sutherland CL, Lawrence WA, Rein-Weston A, Cosman D (2003) ULBP4 is a novel ligand for human NKG2D. Biochem Biophys Res Commun 305:129–135

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Das H, Groh V, Kuijl C, Sugita M, Morita CT, Spies T, Bukowski JF (2001) MICA engagement by human V.2Vd2 T cells enhances their antigen-dependent effector function. Immunity 15:83–93

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Doubrovina ES, Doubrovin MM, Vider E, Sisson RB, O’Reilly RJ, Dupont B, Vyas YM (2003) Evasion from NK cell immunity by MHC class I-chain related molecules expressing colon carcinoma. J Immunol 171:6891–6899

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Eleme K, Taner SB, Onfelt B, Collinson LM, McCann FE, Chalupny NJ, Cosman D, Hopkins C, Magee AI, Davis DM (2004) Cell surface organization of stress-inducible proteins ULBP and MICA that stimulate human NK cells and T cells via NKG2D. J Exp Med 199:1005–1010

    Article  CAS  PubMed  Google Scholar 

  • Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, Hobby P, Sutton B, Tigelaar RE, Hayday AC (2001) Regulation of cutaneous malignancy by γδ T cells. Science 294:605–609

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T (1999) Broad tumor-associated expression and recognition by tumor-derived γδ T cells of MICA and MICB. Proc Natl Acad Sci USA 96:6879–6884

    Article  CAS  PubMed  Google Scholar 

  • Groh V, Rhinehart R, Randolph-Habecker J, Topp MS, Riddell SR, Spies T (2001) Costimulation of CD8 α β T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol 2:255–260

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Groh V, Brühl A, Nelson JL, El-Gabalawi H, Spies T (2003) Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci USA 100, 9452–9457

    Article  CAS  PubMed  Google Scholar 

  • Hamerman JA, Ogasawara K, Lanier LL (2004) Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. J Immunol 172:2001–2005

    CAS  PubMed  Google Scholar 

  • Hankey KG, Drachenberg CB, Papadimitriou JC, Klassen DK, Philosophe B, Bartlett ST, Groh V, Spies T, Mann DL (2002) MIC expression in renal and pancreatic allografts. Transplantation 73:304–306

    Article  CAS  PubMed  Google Scholar 

  • Havran WL, Chien YH, Allison JP (1991) Recognition of self antigens by skin-derived T cells with invariant γ δ antigen receptors. Science 252:1430–1432

    CAS  PubMed  Google Scholar 

  • Houchins JP, Yabe T, McSherry C, Bach FH (1991) 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Lanier LL (2001) On guard—activating NK cell receptors. Nat Immunol 2:23–27

    Article  CAS  PubMed  Google Scholar 

  • Lee JC, Lee KM, Kim DW, Heo DS (2004) Elevated TGF-β1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172:7335–7340

    CAS  PubMed  Google Scholar 

  • Lee N, Llano M, Carretero M, Ishitani A, Navarro F, Lopez-Botet M, Geraghty DE (1998) HLA-E is a major ligand for the natural killer inhibitory receptor CD94/NKG2A. Proc Natl Acad Sci USA 95:5199–5204

    Article  CAS  PubMed  Google Scholar 

  • Li P, Willie ST, Bauer S, Morris DL, Spies T, Strong RK (1999) Crystal structure of the MHC class I homolog MIC-A, a γδ T cell ligand. Immunity 10:577–584

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Li Z, Groh V, Strong RK, Spies T (2000) A single amino acid substitution causes loss of expression of a MICA allele. Immunogenetics 51:246–248

    Article  CAS  PubMed  Google Scholar 

  • Long EO (1999) Regulation of immune responses through inhibitory receptors. Annu Rev Immunol 17:875–904

    Article  CAS  PubMed  Google Scholar 

  • McFarland BJ, Strong RK (2003) Thermodynamic analysis of degererate recognition by the NKG2D immunoreceptor: not induced fit but rigid adaptation. Immunity 19:803–812

    Article  CAS  PubMed  Google Scholar 

  • 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 (2004) Coordinated Induction by IL-15 of a TCR-independent pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357–366

    Article  CAS  PubMed  Google Scholar 

  • Morimoto RI, Sarge KD, Abravaya K (1992) Transcriptional regulation of heat shock genes. J Biol Chem 267: 21987–21990

    CAS  PubMed  Google Scholar 

  • Moser JM, Gibbs J, Jensen PE, Lukacher AE (2002) CD94-NKG2A receptors regulate antiviral CD8+ T cell responses. Nat Immunol 3:189–195

    Article  CAS  PubMed  Google Scholar 

  • Noppen C, Schaefer C, Zajac P, Schutz A, Kocher T, Kloth J, Heberer M, Colonna M, De Libero G, Spagnoli GC (1998) C-type lectin-like receptors in peptide-specific HLA class I-restricted expression and modulation of effector functions in clones sharing identical TCR structure and epitope specificity. Eur J Immunol 28:1134–1142

    Article  CAS  PubMed  Google Scholar 

  • Ota M, Bahram S, Katsuyama Y, Saito S, Nose Y, Sada M, Ando H, Inoko H (2000) On the MICA deleted-MICB null, HLA-B*4801 haplotype. Tissue Antigens 56:268–271

    Article  CAS  PubMed  Google Scholar 

  • Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L, Marcenaro E, Accame L, Malaspina A, Biassoni R, Bottino C, Moretta L, Moretta A (1999) Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J ExpMed 190: 1505–1516

    CAS  Google Scholar 

  • Pessino A, Sivori S, Bottino C, Malaspina A, Morelli L, Moretta L, Biassoni R, Moretta A (1998) Molecular cloning of NKp46, a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J ExpMed 188:953–960

    Article  CAS  Google Scholar 

  • Ploegh HL (1998) Viral strategies of immune evasion. Science 280:248–253

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Radaev S, Kattah M, You Z, Colonna M, Sun PD (2002) Making sense of the diverse ligand recognition by NKG2D. J Immunol 169:6279–6285

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Ravetch JV, Lanier LL (2000) Immune inhibitory receptors. Science 290:84–89

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Russomando AK, Kikuchi M, Candia N, Franco L, Almiron M, Ubalee R, Hirayama K (2002) High frequency of MIC null haplotype (HLA-B48-MICA-del-MICB*0107N) in the Angaite Amerindian community in Paraguay. Immunogenetics 54: 439–441

    Article  PubMed  Google Scholar 

  • Salih HR, Rammensee HG, Steinle A (2002) Down-regulation of MICA on human tumors by proteolytic shedding. J Immunol 169:4098–4102

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Siren, J, Sareneva T, Pirhonen J, Strengell M, Veckman V, Julkunen I, Matikainen S (2004) Cytokine and contact-dependent activation of natural killer cells by influenza A or Sendai virus-infected macrophages. J. Gen Virol 85:2357–2364

    Article  CAS  PubMed  Google Scholar 

  • Spada, FM, Grant EP, Peters PJ, Sugita M, Melian A, Leslie DS, Lee HK, van Donselaar E, Hanson DA, Krensky AM, Majdic O, Porcelli SA, Morita CT, Brenner MB (2000) Self-recognition of CD1 by γδ T cells: implications for innate immunity. J Exp Med 191:937–948

    Article  CAS  PubMed  Google Scholar 

  • Suemizu H, Radosavljevic M, Kimura M, Sadahiro S, Yoshimura S, Bahram S, Inoko H (2002) A basolateral sorting motif in the MICA cytoplasmic tail. Proc Natl Acad Sci USA 99:2971–2976

    Article  CAS  PubMed  Google Scholar 

  • Steinle A, Groh V, Bauer S, Spies T (1998) Diversification, expression and γδ T-cell recognition of evolutionary distant members of the MIC family of major histocompatibility complex class I-related molecules. Proc Natl Acad Sci USA 95:12510–12515

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Stephens HAF (2001) MICA and MICB genes: can the enigma of their polymorphism be resolved? Trends Immunol 22:378–385

    Article  CAS  PubMed  Google Scholar 

  • Sumitran-Holgersson S, Wilczek HE, Holgersson J, Soderstrom K (2002) Identification of the nonclassical HLA molecules, MICA, as targets for humoral immunity associated with irreversible rejection of kidney allografts. Transplantation 74:268–277

    Article  CAS  PubMed  Google Scholar 

  • Tieng V, Le Bouguenec C, du Merle L, Bertheau P, Desreumaux P, Janin A, Charron D, Toubert A (2002) Binding of Escherichia coli adhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related MICA. Proc Natl Acad Sci USA 5:2684–2586

    Google Scholar 

  • Vetter CS, Groh V, thor Straten P, Spies T, Bröcker E-B, Becker J. Expression of stress induced MIC molecules on human melanoma. J Invest Dermatol 118, 600–605, 2002

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Groh V, Spies T (2002) T cell antigen receptor engagement and specificity in the recognition of stress-inducible MIC by human epithelial γδ T cells. J Immumol 169:1236–1240

    CAS  Google Scholar 

  • Wu J, Chalupny NJ, Manley TJ, Riddell SR, Cosman D, Spies T (2003) Intracellular retention of the MHC class I-related chain B ligand of NKG2D by the human CMV UL16 glycoprotein. J Immunol 170:4196–4200

    CAS  PubMed  Google Scholar 

  • Yamamoto K, Fujiyama Y, Andoh A, Bamba T, Okabe H (2001) Oxidative stress increases MICA and MICB gene expression in the human colon carcinoma cell line (CaCo-2). Biochim Biophys Acta 1526:10–12

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA, 98109, USA

    S. González, V. Groh & T. Spies

Authors
  1. S. González
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  2. V. Groh
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  3. T. Spies
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Corresponding author

Correspondence to T. Spies .

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Editors and Affiliations

  1. Atlanta, Georgia

    R.W. Compans

  2. Birmingham, Alabama

    M.D. Cooper

  3. Kyoto

    T. Honjo

  4. Philadelphia, Pennsylvania

    H. Koprowski

  5. Basel

    F. Melchers

  6. La Jolla, California

    M.B.A. Oldstone

  7. Oslo

    S. Olsnes

  8. Bethesda, Maryland

    M. Potter

  9. La Jolla, California

    P.K. Vogt

  10. Munich

    H. Wagner

  11. Laboratory of NK Cells and Innate Immunity, Centre d’Immunologie de Marseille-Luminy (CIML), CNRS-INSERM-Université de la Méditerranée, Campus de Luminy, Case 906, 13288, Marseille Cedex 09, France

    Eric Vivier DVM, PhD.

  12. Department of Pathology and Immunology, Washington University School of Medicine, West Building, Rooms 4724, Box 8118 660 South Euclid Ave, St. Louis, MO, 63110, USA

    Marco Colonna M.D.

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González, S., Groh, V., Spies, T. (2006). Immunobiology of Human NKG2D and Its Ligands. In: Compans, R., et al. Immunobiology of Natural Killer Cell Receptors. Current Topics in Microbiology and Immunology, vol 298. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27743-9_6

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