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

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.

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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.

References

  1. 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).

  2. 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).

  3. 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).

  4. 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).

  5. 5

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

  6. 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).

  7. 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).

  8. 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).

  9. 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).

  10. 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).

  11. 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).

  12. 12

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

  13. 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).

  14. 14

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

  15. 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).

  16. 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).

  17. 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).

  18. 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).

  19. 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).

  20. 20

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

  21. 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).

  22. 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).

  23. 23

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

  24. 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).

  25. 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).

  26. 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).

  27. 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).

  28. 28

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

  29. 29

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

  30. 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).

  31. 31

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

  32. 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).

  33. 33

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

  34. 34

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

  35. 35

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

  36. 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).

  37. 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).

  38. 38

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

  39. 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).

  40. 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).

  41. 41

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

  42. 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).

  43. 43

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

  44. 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).

  45. 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).

  46. 46

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

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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.)

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Correspondence to Shigeo Koyasu.

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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) doi:10.1038/ni729

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