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  • Original Article
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Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells

Abstract

The surface phenotype CD3NK1.1+DX5+CD11cintB220+GR1 has been recently ascribed to a novel subset of mouse leukocytes termed interferon (IFN)-producing killer dendritic cells (IKDCs) that shares functions with natural killer (NK) cells and DCs. Interleukin-15 (IL-15) is critical for NK cells but its relationship with IKDC remained unexplored. An expression cassette encoding human IL-15 (hIL-15) has been transferred by hydrodynamic injection into the liver of mice, resulting in transient expression of the cytokine that is detectable during the first 48 h. hIL-15 hydrodynamic gene transfer resulted in an expansion of NK cells and IKDCs. Relative expansions of IKDCs were more dramatic in the IL-15 gene-transferred hepatic tissue than in the spleen. Adoptively transferred DX5+ cells comprising both NK cells and IKDCs proliferated in response to hydrodynamic injection of hIL-15, indicating that quantitative increases are at least in part the result of proliferation from already differentiated cells. Expansion is accompanied by enhanced cytolytic activity and increased expression of TRAIL and CD137 (4-1BB), without augmenting interferon-γ production. The effects of a single hydrodynamic injection surpassed those of two intraperitoneal doses of the recombinant protein. The novel functional link between circulating IL-15 and IKDCs opens new possibilities to study the biology and applications of this minority cell subset.

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Abbreviations

IKDC:

interferon-producing killer dendritic cell

References

  1. Chan CW, Crafton E, Fan HN, Flook J, Yoshimura K, Skarica M et al. Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity. Nat Med 2006; 12: 207–213.

    Article  CAS  PubMed  Google Scholar 

  2. Taieb J, Chaput N, Menard C, Apetoh L, Ullrich E, Bonmort M et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nat Med 2006; 12: 214–219.

    Article  CAS  PubMed  Google Scholar 

  3. Pillarisetty VG, Katz SC, Bleier JI, Shah AB, Dematteo RP . Natural killer dendritic cells have both antigen presenting and lytic function and in response to CpG produce IFN-gamma via autocrine IL-12. J Immunol 2005; 174: 2612–2618.

    Article  CAS  PubMed  Google Scholar 

  4. Plitas G, Chaudhry UI, Kingham TP, Raab JR, DeMatteo RP . NK dendritic cells are innate immune responders to Listeria monocytogenes infection. J Immunol 2007; 178: 4411–4416.

    Article  CAS  PubMed  Google Scholar 

  5. Welner RS, Pelayo R, Garrett KP, Chen X, Perry SS, Sun XH et al. Interferon-producing killer dendritic cells (IKDC) arise via a unique differentiation pathway from primitive c-kitHiCD62L+ lymphoid progenitors. Blood 2007; 22: 22.

    Google Scholar 

  6. Ullrich E, Bonmort M, Mignot G, Chaput N, Taieb J, Menard C et al. Therapy-induced tumor immunosurveillance involves IFN-producing killer dendritic cells. Cancer Res 2007; 67: 851–853.

    Article  CAS  PubMed  Google Scholar 

  7. Spits H, Lanier LL . Natural killer or dendritic: what's in a name? Immunity 2007; 26: 11–16.

    Article  CAS  PubMed  Google Scholar 

  8. Vosshenrich CA, Lesjean-Pottier S, Hasan M, Richard-Le Goff O, Corcuff E, Mandelboim O et al. CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells. J Exp Med 2007; 204: 2569–2578.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Blasius AL, Barchet W, Cella M, Colonna M . Development and function of murine B220+CD11c+NK1.1+ cells identify them as a subset of NK cells. J Exp Med 2007; 204: 2561–2568.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Caminschi I, Ahmet F, Heger K, Brady J, Nutt SL, Vremec D et al. Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells. J Exp Med 2007; 204: 2579–2590.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Budagian V, Bulanova E, Paus R, Bulfone-Paus S . IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev 2006; 17: 259–280.

    Article  CAS  PubMed  Google Scholar 

  12. Becknell B, Caligiuri MA . Interleukin-2, interleukin-15, and their roles in human natural killer cells. Adv Immunol 2005; 86: 209–239.

    Article  CAS  PubMed  Google Scholar 

  13. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M et al. Reversible defects in natural killer and memory CD8T cell lineages in interleukin 15-deficient mice. J Exp Med 2000; 191: 771–780.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Fehniger TA, Suzuki K, Ponnappan A, VanDeusen JB, Cooper MA, Florea SM et al. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells. J Exp Med 2001; 193: 219–231.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 1998; 9: 669–676.

    Article  CAS  PubMed  Google Scholar 

  16. Koka R, Burkett PR, Chien M, Chai S, Chan F, Lodolce JP et al. Interleukin (IL)-15R[alpha]-deficient natural killer cells survive in normal but not IL-15R[alpha]-deficient mice. J Exp Med 2003; 197: 977–984.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Carson WE, Giri JG, Lindemann MJ, Linett ML, Ahdieh M, Paxton R et al. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med 1994; 180: 1395–1403.

    Article  CAS  PubMed  Google Scholar 

  18. Dubois S, Mariner J, Waldmann TA, Tagaya Y . IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells. Immunity 2002; 17: 537–547.

    Article  CAS  PubMed  Google Scholar 

  19. Waldmann TA . The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 2006; 6: 595–601.

    Article  CAS  PubMed  Google Scholar 

  20. Kobayashi H, Dubois S, Sato N, Sabzevari H, Sakai Y, Waldmann TA et al. Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance. Blood 2005; 105: 721–727.

    Article  CAS  PubMed  Google Scholar 

  21. Niidome T, Huang L . Gene therapy progress and prospects: nonviral vectors. Gene Ther 2002; 9: 1647–1652.

    Article  CAS  PubMed  Google Scholar 

  22. He Y, Pimenov AA, Nayak JV, Plowey J, Falo Jr LD, Huang L . Intravenous injection of naked DNA encoding secreted flt3 ligand dramatically increases the number of dendritic cells and natural killer cells in vivo. Hum Gene Ther 2000; 11: 547–554.

    Article  CAS  PubMed  Google Scholar 

  23. Ortaldo JR, Winkler-Pickett RT, Bere Jr EW, Watanabe M, Murphy WJ, Wiltrout RH . In vivo hydrodynamic delivery of cDNA encoding IL-2: rapid, sustained redistribution, activation of mouse NK cells, and therapeutic potential in the absence of NKT cells. J Immunol 2005; 175: 693–699.

    Article  CAS  PubMed  Google Scholar 

  24. Hazama S, Noma T, Wang F, Iizuka N, Ogura Y, Yoshimura K et al. Tumour cells engineered to secrete interleukin-15 augment anti-tumour immune responses in vivo. Br J Cancer 1999; 80: 1420–1426.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Di Carlo E, Comes A, Basso S, De Ambrosis A, Meazza R, Musiani P et al. The combined action of IL-15 and IL-12 gene transfer can induce tumor cell rejection without T and NK cell involvement. J Immunol 2000; 165: 3111–3118.

    Article  CAS  PubMed  Google Scholar 

  26. Kishida T, Asada H, Itokawa Y, Cui FD, Shin-Ya M, Gojo S et al. Interleukin (IL)-21 and IL-15 genetic transfer synergistically augments therapeutic antitumor immunity and promotes regression of metastatic lymphoma. Mol Ther 2003; 8: 552–558.

    Article  CAS  PubMed  Google Scholar 

  27. Croce M, Meazza R, Orengo AM, Radic L, De Giovanni B, Gambini C et al. Sequential immunogene therapy with interleukin-12- and interleukin-15-engineered neuroblastoma cells cures metastatic disease in syngeneic mice. Clin Cancer Res 2005; 11: 735–742.

    CAS  PubMed  Google Scholar 

  28. Meazza R, Lollini PL, Nanni P, De Giovanni C, Gaggero A, Comes A et al. Gene transfer of a secretable form of IL-15 in murine adenocarcinoma cells: effects on tumorigenicity, metastatic potential and immune response. Int J Cancer 2000; 87: 574–581.

    Article  CAS  PubMed  Google Scholar 

  29. Vera M, Razquin N, Prieto J, Melero I, Fortes P, Gonzalez-Aseguinolaza G . Intratumoral injection of dendritic cells transduced by an SV40-based vector expressing interleukin-15 induces curative immunity mediated by CD8+ T lymphocytes and NK cells. Mol Ther 2005; 12: 950–959.

    Article  CAS  PubMed  Google Scholar 

  30. Stoklasek TA, Schluns KS, Lefrancois L . Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol 2006; 177: 6072–6080.

    Article  CAS  PubMed  Google Scholar 

  31. Suzuki A, McCall S, Choi SS, Sicklick JK, Huang J, Qi Y et al. Interleukin-15 increases hepatic regenerative activity. J Hepatol 2006; 45: 410–418.

    Article  CAS  PubMed  Google Scholar 

  32. Mehal WZ, Azzaroli F, Crispe IN . Immunology of the healthy liver: old questions and new insights. Gastroenterology 2001; 120: 250–260.

    Article  CAS  PubMed  Google Scholar 

  33. Chen L, Calomeni E, Wen J, Ozato K, Shen R, Gao JX . Natural killer dendritic cells are an intermediate of developing dendritic cells. J Leukoc Biol 2007; 1: 1.

    CAS  Google Scholar 

  34. Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L . NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol 1998; 190: 167–172.

    Article  CAS  PubMed  Google Scholar 

  35. Qin L, Ding Y, Pahud DR, Chang E, Imperiale MJ, Bromberg JS . Promoter attenuation in gene therapy: interferon-gamma and tumor necrosis factor-alpha inhibit transgene expression. Hum Gene Ther 1997; 8: 2019–2029.

    Article  CAS  PubMed  Google Scholar 

  36. Wang L, Hernandez-Alcoceba R, Shankar V, Zabala M, Kochanek S, Sangro B et al. Prolonged and inducible transgene expression in the liver using gutless adenovirus: a potential therapy for liver cancer. Gastroenterology 2004; 126: 278–289.

    Article  CAS  PubMed  Google Scholar 

  37. Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD et al. Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci USA 2006; 103: 9166–9171.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Sato N, Patel HJ, Waldmann TA, Tagaya Y . The IL-15/IL-15Ralpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc Natl Acad Sci USA 2007; 104: 588–593.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Chaudhry UI, Plitas G, Burt BM, Kingham TP, Raab JR, DeMatteo RP . NK dendritic cells expanded in IL-15 exhibit antitumor responses in vivo. J Immunol 2007; 179: 4654–4660.

    Article  CAS  PubMed  Google Scholar 

  40. Waldmann TA . Effective cancer therapy through immunomodulation. Annu Rev Med 2006; 57: 65–81.

    Article  CAS  PubMed  Google Scholar 

  41. Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA 2004; 101: 1969–1974.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Waldmann TA . The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol 2006; 6: 595–601.

    Article  CAS  PubMed  Google Scholar 

  43. Maraskovsky E, Brasel K, Teepe M, Roux ER, Lyman SD, Shortman K et al. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med 1996; 184: 1953–1962.

    Article  CAS  PubMed  Google Scholar 

  44. Shortman K, Villadangos JA . Is it a DC, is it an NK? No, it's an IKDC. Nat Med 2006; 12: 167–168.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was financially supported by Ministerio de Educación y Ciencia (MEC-SAF2005-03131), Departamentos de Educación y Salud del Gobierno de Navarra, Redes temáticas de investigación cooperativa and ‘UTE for project FIMA.’ Associazione Italiana per la Ricerca sul Cancro funded SF's work. OM and AAr are recipients of scholarships from Ministerio de Educación y Ciencia and Fondo de Investigación Sanitaria. SH-S is supported by Asociación Española Contra el Cancer.

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Correspondence to S Hervas-Stubbs or I Melero.

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Arina, A., Murillo, O., Dubrot, J. et al. Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells. Gene Ther 15, 473–483 (2008). https://doi.org/10.1038/gt.2008.4

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