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Table of Contents
Vol. 3, No. 3, 2011
Issue release date: April 2011
Section title: Review
J Innate Immun 2011;3:289–297

The Role of Natural Killer Cells in the Defense against Listeriamonocytogenes Lessons from a Rat Model

Naper C.b · Shegarfi H.a · Inngjerdingen M.b · Rolstad B.a
aDepartment of Anatomy, Institute of Basic Medical Sciences, University of Oslo, and bInstitute of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
email Corresponding Author

Dr. Bent Rolstad

Department of Anatomy, Institute of Basic Medical Sciences

University of Oslo

NO–0316 Oslo (Norway)

Tel. +47 2285 1212, E-Mail bent.rolstad@medisin.uio.no


  1. Pamer EG: Immune responses to Listeria monocytogenes. Nat Rev Immunol 2004;4:812–823.
  2. Freitag NE, Port GC, Miner MD: Listeria monocytogenes – from saprophyte to intracellular pathogen. Nat Rev Microbiol 2009;7:623–628.
  3. Cabanes D, Dehoux P, Dussurget O, Frangeul L, Cossart P: Surface proteins and the pathogenic potential of Listeria monocytogenes. Trends Microbiol 2002;10:238–245.
  4. Wing E, Gregory S: Listeria monocytogenes: clinical and experimental update. J Infect Dis 2002;185:S18–S24.
  5. Lecuit M: Human listeriosis and animal models. Microbes Infect 2007;9:1216–1225.
  6. Kaufmann SHE: Immunity to intracellular bacteria. Annu Rev Immunol 1993;11:129–163.
  7. Neuenhahn M, Kerksiek KM, Nauerth M, Suhre MH, Schiemann M, Gebhardt FE, Stemberger C, Panthel K, Schroder S, Chakraborty T, Jung S, Hochrein H, Russmann H, Brocker T, Busch DH: CD8alpha+ dendritic cells are required for efficient entry of Listeria monocytogenes into the spleen. Immunity 2006;25:619–630.
  8. McElroy DS, Ashley TJ, D’Orazio SE: Lymphocytes serve as a reservoir for Listeria monocytogenes growth during infection of mice. Microb Pathog 2009;46:214–221.
  9. Schnupf P, Portnoy DA: Listeriolysin O: a phagosome-specific lysin. Microbes Infect 2007;9:1176–1187.
  10. Posfay-Barbe KM, Wald ER: Listeriosis. Semin Fetal Neonatal Med 2009;14:228–233.
  11. North RJ, Dunn PL, Conlan JW: Murine listeriosis as a model of antimicrobial defense. Immunol Rev 1997;158:27–36.
  12. Miki K, Mackanness GB: The passive transfer of acquired resistance to Listeria monocytogenes. J Exp Med 1964;120:93–103.
  13. Mackaness GB: Cellular resistance to infection. J Exp Med 1962;116:381–406.
  14. Brockstedt DG, Dubensky TW: Promises and challenges for the development of Listeria monocytogenes-based immunotherapies. Expert Rev Vaccines 2008;7:1069–1084.
  15. Bahjat KS, Prell RA, Allen HE, Liu W, Lemmens EE, Leong ML, Portnoy DA, Dubensky TW Jr, Brockstedt DG, Giedlin MA: Activation of immature hepatic NK cells as immunotherapy for liver metastatic disease. J Immunol 2007;179:7376–7384.
  16. Bancroft GJ, Schreiber RD, Unanue ER: Natural immunity: a T-cell-independent pathway of macrophage activation, defined in the SCID mouse. Immunol Rev 1991;124:5–24.
  17. Edelson BT, Unanue ER: Immunity to Listeria infection. Immunity 2000;14:503–512.
  18. Yin J, Ferguson TA: Identification of an IFN-γ-producing neutrophil early in the response to Listeria monocytogenes. J Immunol 2009;182:7069–7073.
  19. Cousens LP, Wing EJ: Innate defenses in the liver during Listeria infection. Immunol Rev 2000;174:150–159.
  20. Serbina NV, Kuziel W, Flavell R, Akira S, Rollins B, Pamer EG: Sequential MyD88-independent and -dependent activation of innate immune responses to intracellular bacterial infection. Immunity 2003;19:891–901.
  21. Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG: TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 2003;19:59–70.
  22. Kurihara T, Warr G, Loy J, Bravo R: Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor. J Exp Med 1997;186:1757–1762.
  23. Kang SJ, Liang HE, Reizis B, Locksley RM: Regulation of hierarchical clustering and activation of innate immune cells by dendritic cells. Immunity 2008;29:819–833.
  24. Shegarfi H, Naper C, Rolstad B, Inngjerdingen M: Listeria monocytogenes infection affects a subset of Ly49-expressing NK cells in the rat. PLoS One 2010;15:e15579.
    External Resources
  25. Berg RE, Crossley E, Murray S, Forman J: Relative contributions of NK and CD8 T cells to IFN-gamma mediated innate immune protection against Listeria monocytogenes. J Immunol 2005;175:1751–1757.
  26. Serbina NV, Pamer EG: Coordinating innate immune cells to optimize microbial killing. Immunity 2008;29:672–674.
  27. Unanue ER: Studies in listeriosis show the strong symbiosis between the innate cellular system and the T-cell response. Immunol Rev 1997;158:11–25.
  28. Humann J, Lenz LL: Activation of naive NK cells in response to Listeria monocytogenes requires IL-18 and contact with infected dendritic cells. J Immunol 2010;184:5172–5178.
  29. Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, Vilcek J, Zinkernagel RM, Aguet M: Immune response in mice that lack the interferon-gamma receptor. Science 1993;259:1742–1745.
  30. Carrero JA, Calderon B, Unanue ER: Lymphocytes are detrimental during the early innate immune response against Listeria monocytogenes. J Exp Med 2006;203:933–940.
  31. O’Connell RM, Saha SK, Vaidya SA, Bruhn KW, Miranda GA, Zarnegar B, Perry AK, Nguyen BO, Lane TF, Taniguchi T, Miller JF, Cheng G: Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J Exp Med 2004;200:437–445.
  32. Auerbuch V, Brockstedt DG, Meyer-Morse N, O’Riordan M, Portnoy DA: Mice lacking the type I interferon receptor are resistant to Listeria monocytogenes. J Exp Med 2004;200:527–533.
  33. Jia T, Leiner I, Dorothee G, Brandl K, Pamer EG: MyD88 and type I interferon receptor-mediated chemokine induction and monocyte recruitment during Listeria monocytogenes infection. J Immunol 2009;183:1271–1278.
  34. Garcia-Peñarrubia P, Koster FT, Kelley RO, McDowell TD, Bankhurst AD: Antibacterial activity of human natural killer cells. J Exp Med 1989;169:99–113.
  35. Bancroft GJ: The role of natural killer cells in innate resistance to infection. Curr Opin Immunol 1993;5:503–510.
  36. Lara-Tejero M, Pamer EG: T cell responses to Listeria monocytogenes. Curr Opin Microbiol 2004;7:45–50.
  37. D’Orazio SE, Halme DG, Ploegh HL, Starnbach MN: Class Ia MHC-deficient BALB/c mice generate CD8+ T cell-mediated protective immunity against Listeria monocytogenes infection. J Immunol 2003;171:291–298.
  38. D’Orazio SEF, Shaw CA, Starnbach MN: H2-M3-restricted CD8+ T cells are not required for MHC class Ib-restricted immunity against Listeria monocytogenes. J Exp Med 2006;203:383–391.
  39. Berg RE, Crossley E, Murray S, Forman J: Memory CD8+ T cells provide innate immune protection against Listeria monocytogenes in the absence of cognate antigen. J Exp Med 2003;198:1583–1593.
  40. Berg RE, Crossley E, Murray S, Forman J: Relative contributions of NK and CD8 T cells to IFN-gamma mediated innate immune protection against Listeria monocytogenes. J Immunol 2005;175:1751–1757.
  41. Bancroft GJ, Schreiber RD, Bosma GC, Bosma MJ, Unanue ER: A T cell-independent mechanism of macrophage activation by interferon-gamma. J Immunol 1987;139:1104–1107.
  42. Hamerman JA, Tchao NK, Lowell CA, Lanier LL: Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat Immunol 2005;6:579–586.
  43. Lodoen MB, Lanier LL: Natural killer cells as an initial defense against pathogens. Curr Opin Immunol 2006;18:391–398.
  44. Teixeira HC, Kaufmann SH: Role of NK1.1+ cells in experimental listeriosis. NK1+ cells are early IFN-gamma producers but impair resistance to Listeria monocytogenes infection. J Immunol 1994;152:1873–1882.
  45. Perona-Wright G, Mohrs K, Szaba FM, Kummer LW, Madan R, Karp CL, Johnson LL, Smiley ST, Mohrs M: Systemic but not local infections elicit immunosuppressive IL-10 production by natural killer cells. Cell Host Microbe 2009;6:503–512.
  46. Vivier E, Ugolini S: Regulatory natural killer cells: new players in the IL-10 anti-inflammatory response. Cell Host Microbe 2009;6:493–495.
  47. Lecuit M, Dramsi S, Gottardi C, Fedor-Chaiken M, Gumbiner B, Cossart P: A single amino acid in E-cadherin responsible for host specificity towards the human pathogen Listeria monocytogenes. EMBO J 1999;18:3956–3963.
  48. Jungi TW, Kunz HW, Gill TJ III, Jungi R: Genetic control of cell-mediated immunity in the rat. 2. Sharing of either the RT1.A or RT1.B locus is sufficient for transfer of antimicrobial resistance. J Immunogenet 1982;9:433–443.
  49. Ioannidu S, Walter L, Dressel R, Gunther E: Physical map and expression profile of genes of the telomeric class I gene region of the rat MHC. J Immunol 2001;166:3957–3965.
  50. Hurt P, Walter L, Sudbrak R, Klages S, Muller I, Shiina T, Inoko H, Lehrach H, Gunther E, Reinhardt R, Himmelbauer H: The genomic sequence and comparative analysis of the rat major histocompatibility complex. Genome Res 2004;14:631–639.
  51. Naper C, Ryan JC, Kirsch R, Butcher GW, Rolstad B, Vaage JT: Genes in two major histocompatibility complex class I regions control selection, phenotype, and function of a rat Ly-49 natural killer cell subset. Eur J Immunol 1999;29:2046–2053.
  52. Rolstad B, Naper C, Lovik G, Vaage JT, Ryan JC, Backman-Petersson E, Kirsch RD, Butcher GW: Rat natural killer cell receptor systems and recognition of MHC class I molecules. Immunol Rev 2001;181:149–157.
  53. Naper C, Hayashi S, Joly E, Butcher GW, Rolstad B, Vaage JT, Ryan JC: Ly49i2 is an inhibitory rat natural killer cell receptor for an MHC class Ia molecule (RT1-A1c). Eur J Immunol 2002;32:2031–2036.
  54. Naper C, Hayashi S, Kveberg L, Niemi EC, Lanier LL, Vaage JT, Ryan JC: Ly-49s3 is a promiscuous activating rat NK cell receptor for nonclassical MHC class I-encoded target ligands. J Immunol 2002;169:22–30.
  55. Naper C, Dai KZ, Kveberg L, Rolstad B, Niemi EC, Vaage JT, Ryan JC: Two structurally related rat Ly49 receptors with opposing functions (Ly49 stimulatory receptor 5 and Ly49 inhibitory receptor 5) recognize nonclassical MHC class Ib-encoded target ligands. J Immunol 2005;174:2702–2711.
  56. Shegarfi H, Sydnes K, Lovik M, Inngjerdingen M, Rolstad B, Naper C: The role of natural killer cells in resistance to the intracellular bacterium Listeria monocytogenes in rats. Scand J Immunol 2009;70:238–244.
  57. Shegarfi H, Dai KZ, Inngjerdingen M, Ryan JC, Vaage JT, Rolstad B, Naper C: The activating rat Ly49s5 receptor responds to increased levels of MHC class Ib molecules on Listeria monocytogenes-infected enteric epithelial cells. Eur J Immunol 2010;40:3535–3543.
  58. Shegarfi H, Dai K-Z, Daws MR, Ryan JC, Vaage JT, Naper C, Rolstad B: The rat NK cell receptors Ly49s4 and Ly49i4 recognize MHC class I molecules on Listeria monocytogenes infected R2 macrophages. J Leukoc Biol 2011, Epub ahead of print.
  59. 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;35:261–272.
  60. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 2004;428:493–521.
  61. Gunther E, Walter L: The major histocompatibility complex of the rat (Rattus norvegicus). Immunogenetics 2001;53:520–542.
  62. Gonzalez-Munoz AL, Le Rolle AF, Brun H, Hedrich HJ, Wedekind D, Powis SJ, Joly E, Butcher GW: A novel instance of class I modification (CIM) affecting two of three rat class I RT1-A molecules within one MHC haplotype. J Immunol 2003;171:274–284.
  63. Joly E, Clarkson C, Howard JC, Butcher GW: Isolation of a functional cDNA encoding the RT1.Au MHC class I heavy chain by a novel PCR-based method. Immunogenetics 1995;41:326–328.
  64. Joly E, Leong L, Coadwell WJ, Clarkson C, Butcher GW: The rat MHC haplotype RT1c expresses two classical class I molecules. J Immunol 1996;157:1551–1558.
  65. Walter L, Gunther E: Physical mapping and evolution of the centromeric class I gene-containing region of the rat MHC. Immunogenetics 2000;51:829–837.
  66. Naper C, Hayashi S, Joly E, Butcher GW, Rolstad B, Vaage JT, Ryan JC: Ly49i2 is an inhibitory rat natural killer cell receptor for an MHC class Ia molecule (RT1-A1c). Eur J Immunol 2002;32:2031–2036.
  67. Roos C, Walter L: Considerable haplotypic diversity in the RT1-CE class I gene region of the rat major histocompatibility complex. Immunogenetics 2005;56:773–777.
  68. Leong L, Le Rolle AM, Deverson EV, Powis SH, Larkins AP, Vaage JT, Stokland AA, Lambracht-Washington D, Rolstad B, Joly E, Butcher GW: RT1.U: identification of a novel active class Ib alloantigen of the rat MHC. J Immunol 1999;162:743–752.
  69. Kveberg L, Dai KZ, Westgaard IH, Daws MR, Fossum S, Naper C, Vaage JT: Two major groups of rat NKR-P1 receptors can be distinguished based on chromosomal localization, phylogenetic analysis and Clr ligand binding. Eur J Immunol 2009;39:541–551.
  70. Yokoyama WM, Plougastel BFM: Immune functions encoded by the natural killer gene complex. Nat Rev Immunol 2003;3:304–316.
  71. Flornes LM, Nylenna O, Saether PC, Daws MR, Dissen E, Fossum S: The complete inventory of receptors encoded by the rat natural killer cell gene complex. Immunogenetics 2010;62:521–530.
  72. Naper C, Vaage JT, Lambracht D, Løvik G, Butcher GW, Wonigeit K, Rolstad B: Alloreactive natural killer cells in the rat. Complex genetics of MHC control. Eur J Immunol 1995;25:1249–1256.
  73. Kveberg L, Back CJ, Dai KZ, Inngjerdingen M, Rolstad B, Ryan JC, Vaage JT, Naper C: The novel inhibitory NKR-P1C receptor and Ly49s3 identify two complementary, functionally distinct NK cell subsets in rats. J Immunol 2006;176:4133–4140.
  74. Kveberg L, Dai KZ, Dissen E, Ryan JC, Rolstad B, Vaage JT, Naper C: Strain-dependent expression of four structurally related rat Ly49 receptors; correlation with NK gene complex haplotype and NK alloreactivity. Immunogenetics 2006;58:905–916.
  75. Reynolds CW, Timonen T, Holden HT, Hansen CT, Herberman RB: Natural killer cell activity in the rat. Analysis of effector cell morphology and effects of interferon on natural killer cell function in the athymic (nude) rat. Eur J Immunol 1982;12:577–582.
  76. Tønnesen B, Rolstad B: In vivo elimination of allogeneic lymphocytes in normal and T-cell-deficient rats. Elimination does not require T cells. Scand J Immunol 1983;17:303–312.
  77. Dissen E, Ryan JC, Seaman WE, Fossum S: An autosomal dominant locus, Nka, mapping to the Ly-49 region of a rat natural killer (NK) gene complex, controls NK cell lysis of allogeneic lymphocytes. J Exp Med 1996;183:2197–2207.
  78. Hamerman JA, Ogasawara K, Lanier LL: Cutting edge: Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. J Immunol 2004;172:2001–2005.
  79. Raulet DH, Guerra N: Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nat Rev Immunol 2009;9:568–580.
  80. Lucas M, Schachterle W, Oberle K, Aichele P, Diefenbach A: Dendritic cells prime natural killer cells by trans-presenting interleukin 15. Immunity 2007;26:503–517.
  81. 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.
  82. 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.
  83. 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;107:159–166.