Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Critical role of IL-15–IL-15R for antigen-presenting cell functions in the innate immune response

Nature Immunology volume 2, pages 1138–1143 (2001)Cite this article

Abstract

Activation of dendritic cells (DCs) and macrophages by infectious agents leads to secretion of interleukin 12 (IL-12), which subsequently induces interferon-γ (IFN-γ) production by multiple cell types that include DCs and macrophages. In turn, IFN-γ acts on macrophages to augment IL-12 secretion and to produce nitric oxide (NO), which eradicates infected microbes. We show here that in cytokine common γ subunit–deficient and/or IL-2 receptor β–deficient mice, production of IL-12, IFN-γ and NO by DCs and macrophages was severely impaired, as was up-regulation of major histocompatibility complex class II and CD40. Similar phenotypes were observed in DCs and macrophages from IL-15–deficient mice but not in those from IL-2–deficient mice. This shows that the IL-15–IL-15R interaction is critical in early activation of antigen-presenting cells and plays an important role in the innate immune system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Presence of macrophages and DCs in the spleens of γc−/−(Y)RAG-2−/−, IL-2Rβ−/−RAG-2−/− and NK-depleted RAG-2−/− mice.
Figure 2: Signals from γc and IL-2Rβ subunits regulate production of IL-12, IFN-γ and NO by APCs.
Figure 3: Impaired up-regulation of MHC class II and CD40 on IL-2Rβ−/− RAG-2−/− and IL-15−/− macrophages.
Figure 4: Essential roles of IL-15 in APC production of IL-12 and the responsiveness of APCs to IL-12.

Similar content being viewed by others

References

  1. Hsieh, C.-S. et al. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547–549 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Manetti, R. et al. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (TH1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J. Exp. Med. 177, 1199–1204 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Trinchieri, G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 13, 251–276 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Buchmeier, N. A. & Schreiber, R. D. Requirement of endogenous interferon-γ production for resolution of Listeria monocytogenes infection. Proc. Natl Acad. Sci. USA 82, 7404–7408 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Harty, J. T. & Bevan, M. J. Specific immunity to Listeria monocytogenes in the absence of IFN γ. Immunity 3, 109–117 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Dai, W. J. et al. Impaired macrophage listericidal and cytokine activities are responsible for the rapid death of Listeria monocytogenes-infected IFN-γ receptor-deficient mice. J. Immunol. 158, 5297–5304 (1997).

    CAS  PubMed  Google Scholar 

  7. Magram, J. et al. IL-12-deficient mice are defective in IFN γ production and type 1 cytokine responses. Immunity 4, 471–481 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Wakil, A. E., Wang, Z.-E., Ryan, J. C., Fowell, D. J. & Locksley, R. M. Interferon γ derived from CD4+ T cells is sufficient to mediate T helper cell type 1 development. J. Exp. Med. 188, 1651–1656 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fultz, M. J., Barber, S. A., Dieffenbach, C. W. & Vogel, S. N. Induction of IFN-γ in macrophages by lipopolysaccharide. Int. Immunol. 5, 1383–1392 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Di Marzio, P., Puddu, P., Conti, L., Belardelli, F. & Gessani, S. Interferon γ upregulates its own gene expression in mouse peritoneal macrophages. J. Exp. Med. 179, 1731–1736 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Song, F., Matsuzaki, G., Mitsuyama, M. & Nomoto, K. Differential effects of viable and killed bacteria on IL-12 expression of macrophages. J. Immunol. 156, 2979–2984 (1996).

    CAS  PubMed  Google Scholar 

  12. Puddu, P. et al. IL–12 induces IFN-γ expression and secretion in mouse peritoneal macrophages. J. Immunol. 159, 3490–3497 (1997).

    CAS  PubMed  Google Scholar 

  13. Munder, M., Mallo, M., Eichmann, K. & Modolell, M. Murine macrophages secrete interferon γ upon combined stimulation with interleukin (IL)-12 and IL-18: A novel pathway of autocrine macrophage activation. J. Exp. Med. 187, 2103–2108 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ohteki, T. et al. Interleukin 12-dependent interferon γ production by CD8α+ lymphoid dendritic cells. J. Exp. Med. 189, 1981–1986 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fukao, T., Masuda, S. & Koyasu, S. Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-γ production by dendritic cells. J. Immunol. 164, 64–71 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Grabstein, K. H. et al. Cloning of a T cell growth factor that interacts with the β chain of the interleukin-2 receptor. Science 264, 965–968 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Burton, J. D. et al. A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc. Natl Acad. Sci. USA 91, 4935–4939 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bamford, R. N. et al. The interleukin (IL) 2 receptor β chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc. Natl Acad. Sci. USA 91, 4940–4944 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Waldmann, T. A. & Tagaya, Y. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu. Rev. Immunol. 17, 19–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771–780 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tagaya, Y., Burton, J. D., Miyamoto, Y. & Waldmann, T. A. Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells. EMBO J. 15 4928–4939 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Espinoza-Delgado et al. Expression and role of p75 interleukin 2 receptor on human monocytes. J. Exp. Med. 171, 1821–1826 (1990).

    Article  CAS  PubMed  Google Scholar 

  24. Jacobsen, F. W., Veiby, O. P., Skjonsberg, C. & Jacobsen, E. W. Novel role of interleukin 7 in myelopoiesis: stimulation of primitive murine hematopoietic progenitor cells. J. Exp. Med. 178, 1777–1782 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Bosco, M. C. et al. Regulation by interleukin-2 (IL-2) and interferon γ of IL-2 receptor γ chain gene expression in human monocytes. Blood 83, 2995–3002 (1994).

    CAS  PubMed  Google Scholar 

  26. Giri, J. G. et al. Identification and cloning of a novel IL-15 binding protein that is structurally related to the α chain of the IL-2 receptor. EMBO J. 14, 3654–3663 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Anderson, D. M. et al. Functional characterization of the human interleukin-15 receptor α chain and close linkage of IL15RA and IL2RA genes. J. Biol. Chem. 270, 29862–29869 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Fukao, T. & Koyasu, S. Expression of functional IL-2 receptors on mature splenic dendritic cells. Eur. J. Immunol. 30, 1453–1457 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor β. Science 268, 1472–1476 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Hochrein, H. et al. Interleukin (IL)-4 is a major regulatory Cytokine governing bioactive IL-12 production by mouse and human dendritic cells. J. Exp. Med. 192, 823–834 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Harald, H. H., Schmidt, W. & Walter, U. NO at work. Cell 78, 919–925 (1994).

    Article  Google Scholar 

  32. MacMicking, J. D. et al. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81, 641–650 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Wei, X.-q. et al. Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375, 408–411 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Dalton, D. K. et al. Multiple defects of immune cell function in mice with disrupted interferon-γ genes. Science 259, 1739–1742 (1993).

    Article  CAS  PubMed  Google Scholar 

  35. Huang, S. et al. Immune response in mice that lack the interferon-γ receptor. Science 259, 1742–1745 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Gately, M. K. et al. The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annu. Rev. Immunol. 16, 495–521 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Grohmann, U. et al. IL-12 acts directly on DC to promote nuclear localization of NF-κB and primes DC for IL-12 production. Immunity 9, 315–323 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Granucci, F. et al. Inducible IL-2 production by dendritic cells revealed by global gene expression analysis. Nature Immunol. 2, 882–888 (2001).

    Article  CAS  Google Scholar 

  39. Fehniger, T. A. et al. IL-15 costimulates the generalized Shwartzman reaction and innate immune IFN-γ production in vivo. J. Immunol. 164, 1643–1647 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Nishimura, H. et al. Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo. J. Exp. Med. 191, 157–170 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Taki, S. et al. Multistage regulation of Th1-type immune responses by the transcription factor IRF-1. Immunity 6, 673–679 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Lohoff, M. et al. Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. Immunity 6, 681–689 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Ogasawara, K. et al. Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature 391, 700–703 (1998).

    Article  CAS  PubMed  Google Scholar 

  44. Ohteki, T. et al. The transcription factor interferon regulatory factor (IRF)-1 is important during the maturation of natural killer 1.1+ T cell receptor-αβ+ (NK1+T) cells, natural killer cells, and intestinal intraepithelial T cells. J. Exp. Med. 187, 967–972 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Noguchi, M. et al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73, 147–157 (1993).

    Article  CAS  PubMed  Google Scholar 

  46. Sugamura, K. et al. The common γ-chain for multiple cytokine receptors. Adv. Immunol. 59, 225–277 (1995).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank K. Sugamura for the Tum122 and TUGm2 mAbs. Supported by the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant 13214095 to T. O.); the Naito Foundation (to T. O.); the Japan Society for the Promotion of Science (13GS0015); a National Grant-in-Aid for the Establishment of a High-Tech Research Center in a private University; a Keio University Special Grant-in-Aid for Innovative Collaborative Research Project; a grant from the Japan Society for the Promotion of Science (JSPS-RFTF-97L00701); a Scientific Frontier Research Grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan; and the Japan Society for the Promotion of Science for Young Scientists (to K. S.)

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160-8582, Tokyo, Japan

    Toshiaki Ohteki, Kazutomo Suzue, Chikako Maki, Takayuki Ota & Shigeo Koyasu

Authors
  1. Toshiaki Ohteki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazutomo Suzue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chikako Maki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takayuki Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shigeo Koyasu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigeo Koyasu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ohteki, T., Suzue, K., Maki, C. et al. Critical role of IL-15–IL-15R for antigen-presenting cell functions in the innate immune response. Nat Immunol 2, 1138–1143 (2001). https://doi.org/10.1038/ni729

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni729

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing