Skip to main content

Advertisement

SpringerLink
Log in

NKG2D in NK and T Cell-Mediated Immunity

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

One of the best characterized NK cell receptors is NKG2D, a highly conserved C-type lectin-like membrane glycoprotein expressed on essentially all NK cells, as well as on γδ-TcR+ T cells and αβ-TcR+ CD8+ T cells, in humans and mice. Here we review recent studies implicating NKG2D in T cell and NK cell-mediated immunity to viruses and tumors, and its potential role in autoimmune diseases and allogeneic bone marrow transplantation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T: Activation of natural killer cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285:727–730, 1999

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  3. 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 17:19–29, 2002

    Article  PubMed  CAS  Google Scholar 

  4. 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. 173:1017–1020, 1991

    Article  PubMed  CAS  Google Scholar 

  5. 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 3:1142–1149, 2002

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. 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 173:2470–2478, 2004

    PubMed  CAS  Google Scholar 

  8. Wu J, Cherwinski H, Spies T, Phillips JH, Lanier LL: DAP10 and DAP12 form distinct, but functionally cooperative, receptor complexes in natural killer cells. J Exp Med 192:1059–1068, 2000

    Article  PubMed  CAS  Google Scholar 

  9. 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 USA 102:7641–7646, 2005

    Article  PubMed  CAS  Google Scholar 

  10. Wu J, Song Y, Bakker ABH, Bauer S, Groh V, Spies T, Lanier LL, Phillips JH: An activating receptor complex on natural killer and T cells formed by NKG2D and DAP10. Science 285:730–732, 1999

    PubMed  CAS  Google Scholar 

  11. Chang C, Dietrich J, Harpur AG, Lindquist JA, Haude A, Loke YW, King A, Colonna M, Trowsdale J, Wilson MJ: Cutting edge: KAP10, a novel transmembrane adapter protein genetically linked to DAP12 but with unique signaling properties. J Immunol 163:4651–4654, 1999

    PubMed  CAS  Google Scholar 

  12. Lanier LL, Corliss BC, Wu J, Leong C, Phillips JH: Immunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cells. Nature 391:703–707, 1998

    Article  PubMed  CAS  Google Scholar 

  13. Cerwenka A, Lanier LL: NKG2D ligands: Unconventional MHC class I-like molecules exploited by viruses and cancer. Tissue Antigens 61:335–343, 2003

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  15. Lanier LL: NK Cell recognition. Annu Rev Immunol 23:225–274, 2005

    Article  PubMed  CAS  Google Scholar 

  16. Malarkannan S, Shih PP, Eden PA, Horng T, Zuberi AR, Christianson G, Roopenian D, Shastri N: The molecular and functional characterization of a dominant minor H antigen, H60. J Immunol 161:3501–3509, 1998

    PubMed  CAS  Google Scholar 

  17. 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 285:727–729, 1999

    Article  PubMed  CAS  Google Scholar 

  18. 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 14:123–133, 2001

    Article  PubMed  CAS  Google Scholar 

  19. Radosavljevic M, Cuillerier B, Wilson MJ, Clement O, Wicker S, Gilfillan S, Beck S, Trowsdale J, Bahram S: A cluster of ten novel MHC class I related genes on human chromosome 6q24.2–q25.3. Genomics 79:114–123, 2002

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  22. 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 12:721–727, 2000

    Article  PubMed  CAS  Google Scholar 

  23. 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 1:119–126, 2000

    Article  PubMed  CAS  Google Scholar 

  24. 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 169:4079–4083, 2002

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  26. 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 197:1245–1253, 2003

    Article  PubMed  CAS  Google Scholar 

  27. Lodoen MB, Abenes G, Umamoto S, Houchins JP, Liu F, Lanier LL: The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60—NKG2D interactions. J Exp Med 200:1075–1081, 2004

    Article  PubMed  CAS  Google Scholar 

  28. 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 3:529–535, 2002

    Article  PubMed  CAS  Google Scholar 

  29. Dandekar AA, O'Malley K, Perlman S: Important roles for gamma interferon and NKG2D in gammadelta T-cell-induced demyelination in T-cell receptor beta-deficient mice infected with a coronavirus. J Virol 79:9388–9396, 2005

    Article  PubMed  CAS  Google Scholar 

  30. 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 USA 93:12445–12450, 1996

    Article  PubMed  CAS  Google Scholar 

  31. Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T: Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci U S A 96:6879–6884, 1999

    Article  PubMed  CAS  Google Scholar 

  32. 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 2:255–260, 2001

    Article  PubMed  CAS  Google Scholar 

  33. Das H, Groh V, Kuijl C, Sugita M, Morita CT, Spies T, Bukowski JF: MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function. Immunity 15:83–93, 2001

    Article  PubMed  CAS  Google Scholar 

  34. Gasser S, Orsulic S, Brown EJ, Raulet DH: The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature, 436:1186–1190, 2005

    Article  PubMed  CAS  Google Scholar 

  35. 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 USA 100:9452–9457, 2003

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  37. 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 201:211–220, 2005

    Article  PubMed  CAS  Google Scholar 

  38. 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 171:902–908, 2003

    PubMed  Google Scholar 

  39. 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 197:1427–1439, 2003

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  41. 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 33:194–203, 2003

    Article  PubMed  CAS  Google Scholar 

  42. Zou Y, Bresnahan W, Taylor RT, Stastny P: Effect of human cytomegalovirus on expression of MHC class I-related chains A. J Immunol 174:3098–3104, 2005

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  44. 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 USA 98:11521–11526, 2001

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  46. Smyth MJ, Swann J, Kelly JM, Cretney E, Yokoyama WM, Diefenbach A, Sayers TJ, Hayakawa Y: NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J Exp Med 200:1325–1335, 2004

    Article  PubMed  CAS  Google Scholar 

  47. 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 175:2167–2173, 2005

    PubMed  CAS  Google Scholar 

  48. Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L, Moretta A: Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: Analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 62:6178–6186, 2002

    PubMed  CAS  Google Scholar 

  49. Westwood JA, Kelly JM, Tanner JE, Kershaw MH, Smyth MJ, Hayakawa Y: Cutting edge: Novel priming of tumor-specific immunity by NKG2D-triggered NK cell-mediated tumor rejection and Th1-independent CD4+ T cell pathway. J Immunol 172:757–761, 2004

    PubMed  CAS  Google Scholar 

  50. Smyth MJ, Swann J, Cretney E, Zerafa N, Yokoyama WM, Hayakawa Y: NKG2D function protects the host from tumor initiation. J Exp Med, 202:583–588, 2005

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  54. Ogasawara K, Hamerman JA, Hsin H, Chikuma S, Bour-Jordan H, Chen T, Pertel T, Carnaud C, Bluestone JA, Lanier LL: Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity 18:41–51, 2003

    Article  PubMed  CAS  Google Scholar 

  55. 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, 6:938–945, 2005

    Article  PubMed  CAS  Google Scholar 

  56. 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 6:928–937, 2005

    Article  PubMed  CAS  Google Scholar 

  57. Wiemann K, Mittrucker HW, Feger U, Welte SA, Yokoyama WM, Spies T, Rammensee HG, Steinle A: Systemic NKG2D down-regulation impairs NK and CD8 T cell responses in vivo. J Immunol 175:720–729, 2005

    PubMed  CAS  Google Scholar 

  58. 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 USA 100:4120–4125, 2003

    Article  PubMed  CAS  Google Scholar 

  59. 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 172:7335–7340, 2004

    PubMed  CAS  Google Scholar 

  60. Kiessling R, Hochman PS, Haller O, Shearer GM, Wigzell H, Cudkowicz G: Evidence for a similar or common mechanism for natural killer cell activity and resistance to hemopoietic grafts. Eur J Immunol 7:655–663, 1977

    PubMed  CAS  Google Scholar 

  61. Lotzova E, Savary CA, Pollack SB: Prevention of rejection of allogeneic bone marrow transplants by NK 1.1 antiserum. Transplantation 35:490–494, 1983

    Article  PubMed  CAS  Google Scholar 

  62. Murphy WJ, Kumar V, Bennett M: Acute rejection of murine bone marrow allografts by natural killer cells and T cells. Differences in kinetics and target antigens recognized. J Exp Med 166:1499–1509, 1987

    CAS  Google Scholar 

  63. Cudkowicz G, Stimpfling JH: Induction of immunity and of unresponsiveness to parental marrow grafts in adult F-1 hybrid mice. Nature 204:450–453, 1964

    PubMed  CAS  Google Scholar 

  64. Cudkowicz G, Bennett M: Peculiar immunobiology of bone marrow allografts. II. Rejection of parental grafts by resistant F 1 hybrid mice. J Exp Med 134:1513–1528, 1971

    PubMed  CAS  Google Scholar 

  65. Rembecki RM, Kumar V, David CS, Bennett M: Bone marrow cell transplants involving intra-H-2 recombinant inbred mouse strains. Evidence that hemopoietic histocompatibility-1 (Hh-1) genes are distinct from H-2D or H-2L. J Immunol 141:2253–2260, 1988

    PubMed  CAS  Google Scholar 

  66. Sentman CL, Kumar V, Bennett M: Rejection of bone marrow cell allografts by natural killer cell subsets: 5E6+ cell specificity for Hh-1 determinant 2 shared by H-2d and H-2f. Eur J Immunol 21:2821–2828, 1991

    PubMed  CAS  Google Scholar 

  67. Yu YYL, Kumar V, Bennett M: Murine natural killer cells and marrow graft rejection. Annu Rev Immunol 10:189–214, 1992

    Article  PubMed  CAS  Google Scholar 

  68. Raziuddin A, Longo DL, Mason L, Ortaldo JR, Murphy WJ: Ly-49 G2+ NK cells are responsible for mediating the rejection of H-2b bone marrow allografts in mice. Int Immunol 8:1833–1839, 1996

    PubMed  CAS  Google Scholar 

  69. Nowbakht P, Ionescu MC, Rohner A, Kalberer CP, Rossy E, Mori L, Cosman D, De Libero G, Wodnar-Filipowicz A: Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias. Blood 105:3615–3622, 2005

    Article  PubMed  CAS  Google Scholar 

  70. Poirot L, Benoist C, Mathis D: Natural killer cells distinguish innocuous and destructive forms of pancreatic islet autoimmunity. Proc Natl Acad Sci USA 101:8102–8107, 2004

    Article  PubMed  CAS  Google Scholar 

  71. 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 21:357–366, 2004

    Article  PubMed  CAS  Google Scholar 

  72. Setiady YY, Pramoonjago P, Tung KS: Requirements of NK cells and proinflammatory cytokines in T cell-dependent neonatal autoimmune ovarian disease triggered by immune complex. J Immunol 173:1051–1058, 2004

    PubMed  CAS  Google Scholar 

  73. Shi FD, Wang HB, Li H, Hong S, Taniguchi M, Link H, Van Kaer L, Ljunggren HG: Natural killer cells determine the outcome of B cell-mediated autoimmunity. Nat Immunol 1:245–251, 2000

    Article  PubMed  CAS  Google Scholar 

  74. 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 21:367–377, 2004

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  76. Anderson MS, Bluestone JA: The NOD mouse: A model of immune dysregulation. Annu Rev Immunol 23:447–485, 2005

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology & Immunology and Cancer Research Institute, University of California, San Francisco, California

    Kouetsu Ogasawara & Lewis L. Lanier

  2. Department of Intractable Diseases, Division of Clinical Immunology, The Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shinjuku-ku, Tokyo, Japan

    Kouetsu Ogasawara

  3. Department of Microbiology & Immunology and Cancer Research Institute, University of California, 513 Parnassus Avenue HSE1001G, P.O. Box 0414, San Francisco, 94143-0414, California

    Lewis L. Lanier

Authors
  1. Kouetsu Ogasawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lewis L. Lanier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lewis L. Lanier.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ogasawara, K., Lanier, L.L. NKG2D in NK and T Cell-Mediated Immunity. J Clin Immunol 25, 534–540 (2005). https://doi.org/10.1007/s10875-005-8786-4

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-005-8786-4

Key Words

Search

Navigation