Skip to main content

Advertisement

SpringerLink
Log in

NK cells after transplantation: friend or foe

  • IMMUNOLOGY AT STANFORD UNIVERSITY
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Natural killer (NK) cells are effector cells of the innate immune system that can lyse target cells without prior sensitization and have an important role in host defense to pathogens and transformed cells. A balance between negative and positive signals transmitted via germ line-encoded inhibitory and activating receptors controls the function of NK cells. Although the concept of “missing-self” would suggest that NK cells could target foreign allografts, the prevailing dogma has been that NK cells are not active participants in the mechanisms that culminate in the rejection of solid organ allografts. Recent studies, however, challenge this conclusion and instead implicate NK cells in contributing to both graft rejection and tolerance to an allograft. In this review, we highlight recent studies with the goal of understanding the complex NK cell interactions that impact alloimmunity.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Caligiuri MA. Human natural killer cells. Blood. 2008;112(3):461–9. doi:10.1182/blood-2007-09-077438 Epub 2008/07/25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nature Rev Immunol. 2001;1(1):41–9.

    Article  CAS  Google Scholar 

  3. Paust S, von Andrian UH. Natural killer cell memory. Nat Immunol. 2011;12(6):500–8.

    Article  CAS  PubMed  Google Scholar 

  4. Lanier LL. Follow the leader: NK cell receptors for classical and nonclassical MHC class I. Cell. 1998;92(6):705–7.

    Article  CAS  PubMed  Google Scholar 

  5. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol. 2003;3(10):781–90.

    Article  CAS  PubMed  Google Scholar 

  6. Yu G, Xu X, Vu MD, Kilpatrick ED, Li XC. NK cells promote transplant tolerance by killing donor antigen-presenting cells. J Exp Med. 2006;203(8):1851–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Horowitz A, Strauss-Albee DM, Leipold M, Kubo J, Nemat-Gorgani N, Dogan OC, Dekker CL, Mackey S, Maecker H, Swan GE, Davis MM, Norman PJ, Guethlein LA, Desai M, Parham P, Blish CA. Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry. Sci Trans Med. 2013;5(208):208ra145. doi:10.1126/scitranslmed.3006702 Epub 2013/10/25.

    Article  CAS  Google Scholar 

  8. Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22(11):633–40.

    Article  CAS  PubMed  Google Scholar 

  9. Parham P. MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol. 2005;5(3):201–14. doi:10.1038/nri1570 Epub 2005/02/19.

    Article  CAS  PubMed  Google Scholar 

  10. Hamerman JA, Ogasawara K, Lanier LL. NK cells in innate immunity. Curr Opin Immunol. 2005;17(1):29–35.

    Article  CAS  PubMed  Google Scholar 

  11. Nylenna O, Naper C, Vaage JT, Woon PY, Gauguier D, Dissen E, Ryan JC, Fossum S. The genes and gene organization of the Ly49 region of the rat natural killer cell gene complex. Eur J Immunol. 2005;35(1):261–72.

    Article  CAS  PubMed  Google Scholar 

  12. Cerwenka A, Lanier LL. Ligands for natural killer cell receptors: redundancy or specificity. Immunol Rev. 2001;181:158–69.

    Article  CAS  PubMed  Google Scholar 

  13. 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(5428):727–9.

    Article  CAS  PubMed  Google Scholar 

  14. Kruse PH, Matta J, Ugolini S, Vivier E. Natural cytotoxicity receptors and their ligands. Immunol Cell Biol. 2013; Epub 2013/12/25. doi:10.1038/icb.2013.98.

  15. Moretta L, Biassoni R, Bottino C, Mingari MC, Moretta A. Human NK-cell receptors. Immunol Today. 2000;21(9):420–2.

    Article  CAS  PubMed  Google Scholar 

  16. Rosental B, Brusilovsky M, Hadad U, Oz D, Appel MY, Afergan F, Yossef R, Rosenberg LA, Aharoni A, Cerwenka A, Campbell KS, Braiman A, Porgador A. Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44. J Immunol. 2011;187(11):5693–702. doi:10.4049/jimmunol.1102267 Epub 2011/10/25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Narni-Mancinelli E, Jaeger BN, Bernat C, Fenis A, Kung S, De Gassart A, Mahmood S, Gut M, Heath SC, Estelle J, Bertosio E, Vely F, Gastinel LN, Beutler B, Malissen B, Malissen M, Gut IG, Vivier E, Ugolini S. Tuning of natural killer cell reactivity by NKp46 and Helios calibrates T cell responses. Science. 2012;335(6066):344–8. doi:10.1126/science.1215621 Epub 2012/01/24.

    Article  CAS  PubMed  Google Scholar 

  18. Pessino A, Sivori S, Bottino C, Malaspina A, Morelli L, Moretta L, Biassoni R, Moretta A. Molecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicity. J Exp Med. 1998;188(5):953–60 Epub 1998/09/09.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Vitale M, Bottino C, Sivori S, Sanseverino L, Castriconi R, Marcenaro E, Augugliaro R, Moretta L, Moretta A. 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. 1998;187(12):2065–72 Epub 1998/06/24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. 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. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med. 1999;190(10):1505–16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Biassoni R, Pessino A, Bottino C, Pende D, Moretta L, Moretta A. The murine homologue of the human NKp46, a triggering receptor involved in the induction of natural cytotoxicity. Eur J Immunol. 1999;29(3):1014–20.

    Article  CAS  PubMed  Google Scholar 

  22. Falco M, Cantoni C, Bottino C, Moretta A, Biassoni R. Identification of the rat homologue of the human NKp46 triggering receptor. Immunol Lett. 1999;68(2–3):411–4.

    Article  CAS  PubMed  Google Scholar 

  23. Hollyoake M, Campbell RD, Aguado B. NKp30 (NCR3) is a pseudogene in 12 inbred and wild mouse strains, but an expressed gene in Mus caroli. Mol Biol Evol. 2005;22(8):1661–72.

    Article  CAS  PubMed  Google Scholar 

  24. Hsieh CL, Ogura Y, Obara H, Ali UA, Rodriguez GM, Nepomuceno RR, Martinez OM, Krams SM. Identification, cloning, and characterization of a novel rat natural killer receptor, RNKP30: a molecule expressed in liver allografts. Transplantation. 2004;77(1):121–8.

    Article  CAS  PubMed  Google Scholar 

  25. Moretta A, Biassoni R, Bottino C, Mingari MC, Moretta L. Natural cytotoxicity receptors that trigger human NK-cell-mediated cytolysis. Immunol Today. 2000;21(5):228–34.

    Article  CAS  PubMed  Google Scholar 

  26. Arnon TI, Achdout H, Levi O, Markel G, Saleh N, Katz G, Gazit R, Gonen-Gross T, Hanna J, Nahari E, Porgador A, Honigman A, Plachter B, Mevorach D, Wolf DG, Mandelboim O. Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat Immunol. 2005;6(5):515–23.

    Article  CAS  PubMed  Google Scholar 

  27. Draghi M, Pashine A, Sanjanwala B, Gendzekhadze K, Cantoni C, Cosman D, Moretta A, Valiante NM, Parham P. NKp46 and NKG2D recognition of infected dendritic cells is necessary for NK cell activation in the human response to influenza infection. J Immunol. 2007;178(5):2688–98.

    Article  CAS  PubMed  Google Scholar 

  28. Mandelboim O, Lieberman N, Lev M, Paul L, Arnon TI, Bushkin Y, Davis DM, Strominger JL, Yewdell JW, Porgador A. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature. 2001;409(6823):1055–60.

    Article  CAS  PubMed  Google Scholar 

  29. Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A. Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity. 2007;27(6):965–74.

    Article  CAS  PubMed  Google Scholar 

  30. Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B, Haldeman B, Ostrander CD, Kaifu T, Chabannon C, Moretta A, West R, Xu W, Vivier E, Levin SD. The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med. 2009;206(7):1495–503.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Baychelier F, Sennepin A, Ermonval M, Dorgham K, Debre P, Vieillard V. Identification of a cellular ligand for the natural cytotoxicity receptor NKp44. Blood. 2013;122(17):2935–42. doi:10.1182/blood-2013-03-489054 Epub 2013/08/21.

    Article  CAS  PubMed  Google Scholar 

  32. Vivier E, Nunes JA, Vely F. Natural killer cell signaling pathways. Science. 2004;306(5701):1517–9.

    Article  CAS  PubMed  Google Scholar 

  33. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med. 2002;195(3):327–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med. 2002;195(3):343–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Piccioli D, Sbrana S, Melandri E, Valiante NM. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med. 2002;195(3):335–41 Epub 2002/02/06.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A. Dendritic cells prime natural killer cells by trans-presenting Interleukin 15. Immunity. 2007;26(4):503–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Spaggiari GM, Carosio R, Pende D, Marcenaro S, Rivera P, Zocchi MR, Moretta L, Poggi A. NK cell-mediated lysis of autologous antigen-presenting cells is triggered by the engagement of the phosphatidylinositol 3-kinase upon ligation of the natural cytotoxicity receptors NKp30 and NKp46. Eur J Immunol. 2001;31(6):1656–65.

    Article  CAS  PubMed  Google Scholar 

  38. Hayakawa Y, Screpanti V, Yagita H, Grandien A, Ljunggren HG, Smyth MJ, Chambers BJ. NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy. J Immunol. 2004;172(1):123–9.

    Article  CAS  PubMed  Google Scholar 

  39. Ferlazzo G, Morandi B, D’Agostino A, Meazza R, Melioli G, Moretta A, Moretta L. The interaction between NK cells and dendritic cells in bacterial infections results in rapid induction of NK cell activation and in the lysis of uninfected dendritic cells. Eur J Immunol. 2003;33(2):306–13.

    Article  CAS  PubMed  Google Scholar 

  40. Wai LE, Garcia JA, Martinez OM, Krams SM. Distinct roles for the NK cell-activating receptors in mediating interactions with dendritic cells and tumor cells. J Immunol. 2011;186(1):222–9. doi:10.4049/jimmunol.1002597.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Ferlazzo G, Thomas D, Lin SL, Goodman K, Morandi B, Muller WA, Moretta A, Munz C. The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J Immunol. 2004;172(3):1455–62.

    Article  CAS  PubMed  Google Scholar 

  42. Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol. 2002;2(12):957–64.

    Article  CAS  PubMed  Google Scholar 

  43. Heidecke CD, Araujo JL, Kupiec-Weglinski JW, Abbud-Filho M, Araneda D, Stadler J, Siewert J, Strom TB, Tilney NL. Lack of evidence for an active role for natural killer cells in acute rejection of organ allografts. Transplantation. 1985;40(4):441–4.

    Article  CAS  PubMed  Google Scholar 

  44. Shelton MW, Walp LA, Basler JT, Uchiyama K, Hanto DW. Mediation of skin allograft rejection in scid mice by CD4+ and CD8+ T cells. Transplantation. 1992;54(2):278–86.

    Article  CAS  PubMed  Google Scholar 

  45. Bingaman AW, Ha J, Waitze SY, Durham MM, Cho HR, Tucker-Burden C, Hendrix R, Cowan SR, Pearson TC, Larsen CP. Vigorous allograft rejection in the absence of danger. J Immunol. 2000;164(6):3065–71.

    Article  CAS  PubMed  Google Scholar 

  46. Kroemer A, Xiao X, Degauque N, Edtinger K, Wei H, Demirci G, Li XC. The innate NK cells, allograft rejection, and a key role for IL-15. J Immunol. 2008;180(12):7818–26.

    Article  CAS  PubMed  Google Scholar 

  47. Auchincloss H Jr, Sachs DH. Xenogeneic transplantation. Annu Rev Immunol. 1998;16:433–70.

    Article  CAS  PubMed  Google Scholar 

  48. Blakely ML, Van der Werf WJ, Berndt MC, Dalmasso AP, Bach FH, Hancock WW. Activation of intragraft endothelial and mononuclear cells during discordant xenograft rejection. Transplantation. 1994;58(10):1059–66.

    Article  CAS  PubMed  Google Scholar 

  49. Gourlay WA, Chambers WH, Monaco AP, Maki T. Importance of natural killer cells in the rejection of hamster skin xenografts. Transplantation. 1998;65(5):727–34.

    Article  CAS  PubMed  Google Scholar 

  50. Manilay JO, Sykes M. Natural killer cells and their role in graft rejection. Curr Opin Immunol. 1998;10(5):532–8.

    Article  CAS  PubMed  Google Scholar 

  51. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, Posati S, Rogaia D, Frassoni F, Aversa F, Martelli MF, Velardi A. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295(5562):2097–100.

    Article  CAS  PubMed  Google Scholar 

  52. Obara H, Nagasaki K, Hsieh CL, Ogura Y, Esquivel CO, Martinez OM, Krams SM. IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses. Am J Transplant. 2005;5(9):2094–103.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Ito A, Shimura H, Nitahara A, Tomiyama K, Ito M, Kanekura T, Okumura K, Yagita H, Kawai K. NK cells contribute to the skin graft rejection promoted by CD4+ T cells activated through the indirect allorecognition pathway. Int Immunol. 2008;20(10):1343–9.

    Article  CAS  PubMed  Google Scholar 

  54. Uehara S, Chase CM, Kitchens WH, Rose HS, Colvin RB, Russell PS, Madsen JC. NK cells can trigger allograft vasculopathy: the role of hybrid resistance in solid organ allografts. J Immunol. 2005;175(5):3424–30.

    Article  CAS  PubMed  Google Scholar 

  55. Pham B, Piard-Ruster K, Silva R, Gallo A, Esquivel CO, Martinez OM, Krams SM. Changes in natural killer cell subsets in pediatric liver transplant recipients. Pediatr Transplant. 2012;16(2):176–82. doi:10.1111/j.1399-3046.2012.01653.x Epub 2012/03/01.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Kummer JA, Wever PC, Kamp AM, ten Berge IJ, Hack CE, Weening JJ. Expression of granzyme A and B proteins by cytotoxic lymphocytes involved in acute renal allograft rejection. Kidney Int. 1995;47(1):70–7.

    Article  CAS  PubMed  Google Scholar 

  57. Yoneda O, Imai T, Goda S, Inoue H, Yamauchi A, Okazaki T, Imai H, Yoshie O, Bloom ET, Domae N, Umehara H. Fractalkine-mediated endothelial cell injury by NK cells. J Immunol. 2000;164(8):4055–62.

    Article  CAS  PubMed  Google Scholar 

  58. Salazar-Mather TP, Hamilton TA, Biron CA. A chemokine-to-cytokine-to-chemokine cascade critical in antiviral defense. J Clin Investig. 2000;105(7):985–93.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Oliva A, Kinter AL, Vaccarezza M, Rubbert A, Catanzaro A, Moir S, Monaco J, Ehler L, Mizell S, Jackson R, Li Y, Romano JW, Fauci AS. Natural killer cells from human immunodeficiency virus (HIV)-infected individuals are an important source of CC-chemokines and suppress HIV-1 entry and replication in vitro. J Clin Investig. 1998;102(1):223–31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Kondo T, Morita K, Watarai Y, Auerbach MB, Taub DD, Novick AC, Toma H, Fairchild RL. Early increased chemokine expression and production in murine allogeneic skin grafts is mediated by natural killer cells. Transplantation. 2000;69(5):969–77.

    Article  CAS  PubMed  Google Scholar 

  61. Hancock WW, Gao W, Csizmadia V, Faia KL, Shemmeri N, Luster AD. Donor-derived IP-10 initiates development of acute allograft rejection. J Exp Med. 2001;193(8):975–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Hancock WW, Gao W, Faia KL, Csizmadia V. Chemokines and their receptors in allograft rejection. Curr Opin Immunol. 2000;12(5):511–6.

    Article  CAS  PubMed  Google Scholar 

  63. Fehniger TA, Herbein G, Yu H, Para MI, Bernstein ZP, O’Brien WA, Caligiuri MA. Natural killer cells from HIV-1+ patients produce C–C chemokines and inhibit HIV-1 infection. J Immunol. 1998;161(11):6433–8.

    CAS  PubMed  Google Scholar 

  64. Maier S, Tertilt C, Chambron N, Gerauer K, Huser N, Heidecke CD, Pfeffer K. Inhibition of natural killer cells results in acceptance of cardiac allografts in CD28-/- mice. Nat Med. 2001;7(5):557–62.

    Article  CAS  PubMed  Google Scholar 

  65. Crome SQ, Lang PA, Lang KS, Ohashi PS. Natural killer cells regulate diverse T cell responses. Trends Immunol. 2013;34(7):342–9. doi:10.1016/j.it.2013.03.002 Epub 2013/04/23.

    Article  CAS  PubMed  Google Scholar 

  66. McNerney ME, Lee KM, Zhou P, Molinero L, Mashayekhi M, Guzior D, Sattar H, Kuppireddi S, Wang CR, Kumar V, Alegre ML. Role of natural killer cell subsets in cardiac allograft rejection. Am J Transplant. 2006;6(3):505–13.

    Article  CAS  PubMed  Google Scholar 

  67. Benichou G, Yamada Y, Aoyama A, Madsen JC. Natural killer cells in rejection and tolerance of solid organ allografts. Curr Opin Organ Transplant. 2011;16(1):47–53. doi:10.1097/MOT.0b013e32834254cf Epub 2010/12/16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Hirohashi T, Chase CM, Della Pelle P, Sebastian D, Alessandrini A, Madsen JC, Russell PS, Colvin RB. A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant. 2012;12(2):313–21. doi:10.1111/j.1600-6143.2011.03836.x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Sivori S, Carlomagno S, Falco M, Romeo E, Moretta L, Moretta A. Natural killer cells expressing the KIR2DS1-activating receptor efficiently kill T-cell blasts and dendritic cells: implications in haploidentical HSCT. Blood. 2011;117(16):4284–92. doi:10.1182/blood-2010-10-316125 Epub 2011/03/01.

    Article  CAS  PubMed  Google Scholar 

  70. Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, Elford AR, Dhanji S, Shaabani N, Tran CW, Dissanayake D, Rahbar R, Ghazarian M, Brustle A, Fine J, Chen P, Weaver CT, Klose C, Diefenbach A, Haussinger D, Carlyle JR, Kaech SM, Mak TW, Ohashi PS. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proc Natl Acad Sci U S A. 2012;109(4):1210–5. doi:10.1073/pnas.1118834109 Epub 2011/12/15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Waggoner SN, Taniguchi RT, Mathew PA, Kumar V, Welsh RM. Absence of mouse 2B4 promotes NK cell-mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis. J Clin Investig. 2010;120(6):1925–38. doi:10.1172/JCI41264 Epub 2010/05/05.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Zecher D, Li Q, Oberbarnscheidt MH, Demetris AJ, Shlomchik WD, Rothstein DM, Lakkis FG. NK cells delay allograft rejection in lymphopenic hosts by downregulating the homeostatic proliferation of CD8+ T cells. J Immunol. 2010;184(12):6649–57. doi:10.4049/jimmunol.0903729 Epub 2010/05/21.

    Article  CAS  PubMed  Google Scholar 

  73. Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack A, Negrin RS. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood. 2010;115(21):4293–301. doi:10.1182/blood-2009-05-222190 Epub 2010/03/18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Beilke JN, Kuhl NR, Van Kaer L, Gill RG. NK cells promote islet allograft tolerance via a perforin-dependent mechanism. Nat Med. 2005;11(10):1059–65. doi:10.1038/nm1296.

    Article  CAS  PubMed  Google Scholar 

  75. Lozano JJ, Pallier A, Martinez-Llordella M, Danger R, Lopez M, Giral M, Londono MC, Rimola A, Soulillou JP, Brouard S, Sanchez-Fueyo A. Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and kidney recipients. Am J Transplant. 2011;11(9):1916–26. doi:10.1111/j.1600-6143.2011.03638.x.

    Article  CAS  PubMed  Google Scholar 

  76. Kim J, Chang CK, Hayden T, Liu FC, Benjamin J, Hamerman JA, Lanier LL, Kang SM. The activating immunoreceptor NKG2D and its ligands are involved in allograft transplant rejection. J Immunol. 2007;179(10):6416–20.

    Article  CAS  PubMed  Google Scholar 

  77. 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(9):938–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Zhuo M, Fujiki M, Wang M, Piard-Ruster K, Wai LE, Wei L, Martinez OM, Krams SM. Identification of the rat NKG2D ligands, RAE1L and RRLT, and their role in allograft rejection. Eur J Immunol. 2010;40(6):1748–57. doi:10.1002/eji.200939779.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Hankey KG, Drachenberg CB, Papadimitriou JC, Klassen DK, Philosophe B, Bartlett ST, Groh V, Spies T, Mann DL. MIC expression in renal and pancreatic allografts. Transplantation. 2002;73(2):304–6.

    Article  CAS  PubMed  Google Scholar 

  80. Suarez-Alvarez B, Lopez-Vazquez A, Diaz-Pena R, Diaz-Molina B, Blanco-Garcia RM, Alvarez-Lopez MR, Lopez-Larrea C. Post-transplant soluble MICA and MICA antibodies predict subsequent heart graft outcome. Transpl Immunol. 2006;17(1):43–6.

    Article  CAS  PubMed  Google Scholar 

  81. Lindvall O, Kokaia Z. Stem cells in human neurodegenerative disorders–time for clinical translation? J Clin Investig. 2010;120(1):29–40. doi:10.1172/JCI40543 Epub 2010/01/07.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  82. Ormerod BK, Palmer TD, Caldwell MA. Neurodegeneration and cell replacement. Philos Trans R Soc Lond B Biol Sci. 2008;363(1489):153–70. doi:10.1098/rstb.2006.2018 Epub 2007/03/03.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Phillips LK, Gould EA, Babu H, Krams SM, Palmer TD, Martinez OM. Natural killer cell-activating receptor NKG2D mediates innate immune targeting of allogeneic neural progenitor cell grafts. Stem Cells. 2013;31(9):1829–39. doi:10.1002/stem.1422 Epub 2013/06/05.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Dressel R, Nolte J, Elsner L, Novota P, Guan K, Streckfuss-Bomeke K, Hasenfuss G, Jaenisch R, Engel W. Pluripotent stem cells are highly susceptible targets for syngeneic, allogeneic, and xenogeneic natural killer cells. FASEB J Off Publ Fed Am Soc Exp Biol. 2010;24(7):2164–77. doi:10.1096/fj.09-134957 Epub 2010/02/11.

    CAS  Google Scholar 

  85. Davis DM, Chiu I, Fassett M, Cohen GB, Mandelboim O, Strominger JL. The human natural killer cell immune synapse. Proc Natl Acad Sci U S A. 1999;96(26):15062–7 Epub 1999/12/28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Dustin ML, Long EO. Cytotoxic immunological synapses. Immunol Rev. 2010;235(1):24–34. doi:10.1111/j.0105-2896.2010.00904.x.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Gross CC, Brzostowski JA, Liu D, Long EO. Tethering of intercellular adhesion molecule on target cells is required for LFA-1-dependent NK cell adhesion and granule polarization. J Immunol. 2010;185(5):2918–26. doi:10.4049/jimmunol.1000761 Epub 2010/08/03.

    Article  CAS  PubMed  Google Scholar 

  88. Bryceson YT, March ME, Barber DF, Ljunggren HG, Long EO. Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J Exp Med. 2005;202(7):1001–12. doi:10.1084/jem.20051143 Epub 2005/10/06.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Banerjee PP, Pandey R, Zheng R, Suhoski MM, Monaco-Shawver L, Orange JS. Cdc42-interacting protein-4 functionally links actin and microtubule networks at the cytolytic NK cell immunological synapse. J Exp Med. 2007;204(10):2305–20. doi:10.1084/jem.20061893 Epub 2007/09/06.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Orange JS, Harris KE, Andzelm MM, Valter MM, Geha RS, Strominger JL. The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc Natl Acad Sci USA. 2003;100(24):14151–6. doi:10.1073/pnas.1835830100 Epub 2003/11/13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Carpen O, Virtanen I, Lehto VP, Saksela E. Polarization of NK cell cytoskeleton upon conjugation with sensitive target cells. J Immunol. 1983;131(6):2695–8 Epub 1983/12/01.

    CAS  PubMed  Google Scholar 

  92. Kupfer A, Dennert G, Singer SJ. Polarization of the Golgi apparatus and the microtubule-organizing center within cloned natural killer cells bound to their targets. Proc Natl Acad Sci U S A. 1983;80(23):7224–8 Epub 1983/12/01.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Burshtyn DN, Shin J, Stebbins C, Long EO. Adhesion to target cells is disrupted by the killer cell inhibitory receptor. Curr Biol CB. 2000;10(13):777–80 Epub 2000/07/19.

    Article  CAS  PubMed  Google Scholar 

  94. Huse M, Catherine Milanoski S, Abeyweera TP. Building tolerance by dismantling synapses: inhibitory receptor signaling in natural killer cells. Immunol Rev. 2013;251(1):143–53. doi:10.1111/imr.12014 Epub 2013/01/03.

    Article  PubMed  CAS  Google Scholar 

  95. Abeyweera TP, Kaissar M, Huse M. Inhibitory receptor signaling destabilizes immunological synapse formation in primary NK cells. Front Immunol. 2013;4:410. doi:10.3389/fimmu.2013.00410 Epub/12/19.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  96. Vyas YM, Mehta KM, Morgan M, Maniar H, Butros L, Jung S, Burkhardt JK, Dupont B. 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(8):4358–67 Epub/10/10.

    Article  CAS  PubMed  Google Scholar 

  97. Roda-Navarro P, Mittelbrunn M, Ortega M, Howie D, Terhorst C, Sanchez-Madrid F, Fernandez-Ruiz E. Dynamic redistribution of the activating 2B4/SAP complex at the cytotoxic NK cell immune synapse. J Immunol. 2004;173(6):3640–6 Epub/09/10.

    Article  CAS  PubMed  Google Scholar 

  98. Schleinitz N, March ME, Long EO. Recruitment of activation receptors at inhibitory NK cell immune synapses. PLoS ONE. 2008;3(9):e3278. doi:10.1371/journal.pone.0003278 Epub/09/27.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  99. Pageon SV, Cordoba SP, Owen DM, Rothery SM, Oszmiana A, Davis DM. Superresolution microscopy reveals nanometer-scale reorganization of inhibitory natural killer cell receptors upon activation of NKG2D. Sci Signal. 2013;6(285):ra62. doi:10.1126/scisignal.2003947 Epub/07/25.

    Article  PubMed  CAS  Google Scholar 

  100. Brown AC, Oddos S, Dobbie IM, Alakoskela JM, Parton RM, Eissmann P, Neil MA, Dunsby C, French PM, Davis I, Davis DM. Remodelling of cortical actin where lytic granules dock at natural killer cell immune synapses revealed by super-resolution microscopy. PLoS Biol. 2011;9(9):e1001152. doi:10.1371/journal.pbio.1001152 Epub/09/21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Rak GD, Mace EM, Banerjee PP, Svitkina T, Orange JS. Natural killer cell lytic granule secretion occurs through a pervasive actin network at the immune synapse. PLoS Biol. 2011;9(9):e1001151. doi:10.1371/journal.pbio.1001151 Epub/09/21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Eissmann P, Davis DM. Inhibitory and regulatory immune synapses. Curr Top Microbiol Immunol. 2010;340:63–79. doi:10.1007/978-3-642-03858-7_4 Epub 2009/12/05.

    CAS  PubMed  Google Scholar 

  103. Mace EM, Orange JS. Multiple distinct NK-cell synapses. Blood. 2011;118(25):6475–6. doi:10.1182/blood-2011-10-381392 Epub/12/17.

    Article  CAS  PubMed  Google Scholar 

  104. Borg C, Jalil A, Laderach D, Maruyama K, Wakasugi H, Charrier S, Ryffel B, Cambi A, Figdor C, Vainchenker W, Galy A, Caignard A, Zitvogel L. NK cell activation by dendritic cells (DCs) requires the formation of a synapse leading to IL-12 polarization in DCs. Blood. 2004;104(10):3267–75. doi:10.1182/blood-2004-01-0380 Epub/07/10.

    Article  CAS  PubMed  Google Scholar 

  105. Nedvetzki S, Sowinski S, Eagle RA, Harris J, Vely F, Pende D, Trowsdale J, Vivier E, Gordon S, Davis DM. Reciprocal regulation of human natural killer cells and macrophages associated with distinct immune synapses. Blood. 2007;109(9):3776–85. doi:10.1182/blood-2006-10-052977 Epub/01/16.

    Article  CAS  PubMed  Google Scholar 

  106. Mortier E, Woo T, Advincula R, Gozalo S, Ma A. IL-15Ralpha chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation. J Exp Med. 2008;205(5):1213–25. doi:10.1084/jem.20071913 Epub/05/07.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Brilot F, Strowig T, Roberts SM, Arrey F, Munz C. NK cell survival mediated through the regulatory synapse with human DCs requires IL-15Ralpha. J Clin Investig. 2007;117(11):3316–29. doi:10.1172/JCI31751 Epub/10/20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Semino C, Angelini G, Poggi A, Rubartelli A. NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1. Blood. 2005;106(2):609–16. doi:10.1182/blood-2004-10-3906 Epub/04/02.

    Article  CAS  PubMed  Google Scholar 

  109. Rossy J, Pageon SV, Davis DM, Gaus K. Super-resolution microscopy of the immunological synapse. Curr Opin Immunol. 2013;25(3):307–12. doi:10.1016/j.coi.2013.04.002 Epub 2013/06/12.

    Article  CAS  PubMed  Google Scholar 

  110. Min-Oo G, Kamimura Y, Hendricks DW, Nabekura T, Lanier LL. Natural killer cells: walking three paths down memory lane. Trends Immunol. 2013;34(6):251–8. doi:10.1016/j.it.2013.02.005 Epub/03/19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Rolle A, Pollmann J, Cerwenka A. Memory of infections: an emerging role for natural killer cells. PLoS Pathog. 2013;9(9):e1003548. doi:10.1371/journal.ppat.1003548 Epub/10/03.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  112. Lopez-Verges S, Milush JM, Schwartz BS, Pando MJ, Jarjoura J, York VA, Houchins JP, Miller S, Kang SM, Norris PJ, Nixon DF, Lanier LL. Expansion of a unique CD57(+)NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. Proc Natl Acad Sci USA. 2011;108(36):14725–32. doi:10.1073/pnas.1110900108 Epub/08/10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Wai LE, Fujiki M, Takeda S, Martinez OM, Krams SM. Rapamycin, but not cyclosporine or FK506, alters natural killer cell function. Transplantation. 2008;85(1):145–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Kudlacz E, Perry B, Sawyer P, Conklyn M, McCurdy S, Brissette W, Flanagan M, Changelian P. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant. 2004;4(1):51–7.

    Article  CAS  PubMed  Google Scholar 

  115. Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, Rizzuti BJ, Sawyer PS, Perry BD, Brissette WH, McCurdy SP, Kudlacz EM, Conklyn MJ, Elliott EA, Koslov ER, Fisher MB, Strelevitz TJ, Yoon K, Whipple DA, Sun J, Munchhof MJ, Doty JL, Casavant JM, Blumenkopf TA, Hines M, Brown MF, Lillie BM, Subramanyam C, Shang-Poa C, Milici AJ, Beckius GE, Moyer JD, Su C, Woodworth TG, Gaweco AS, Beals CR, Littman BH, Fisher DA, Smith JF, Zagouras P, Magna HA, Saltarelli MJ, Johnson KS, Nelms LF, Des Etages SG, Hayes LS, Kawabata TT, Finco-Kent D, Baker DL, Larson M, Si MS, Paniagua R, Higgins J, Holm B, Reitz B, Zhou YJ, Morris RE, O’Shea JJ, Borie DC. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science. 2003;302(5646):875–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by funding from the National Institutes of Health Grants AI084939, AI044095, and AI104230; The Stanford Institute for Immunity, Transplantation, and Infection Interdisciplinary Research Program Award; and The Transplantation Society International Basic Science Research Exchange Fellowship.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Abdominal Transplantation, Department of Surgery and Stanford Immunology, Stanford University School of Medicine, Stanford, CA, USA

    Uzi Hadad, Olivia Martinez & Sheri M. Krams

  2. The Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev, P.O.B. 653, 84105, Beersheba, Israel

    Uzi Hadad

Authors
  1. Uzi Hadad
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Olivia Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sheri M. Krams
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sheri M. Krams.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hadad, U., Martinez, O. & Krams, S.M. NK cells after transplantation: friend or foe. Immunol Res 58, 259–267 (2014). https://doi.org/10.1007/s12026-014-8493-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8493-4

Keywords

Search

Navigation