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Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses

Nature Immunology volume 13, pages 659–666 (2012)Cite this article

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Abstract

Although the mechanisms by which innate pathogen-recognition receptors enhance adaptive immune responses are increasingly well understood, whether signaling events from distinct classes of receptors affect each other in modulating adaptive immunity remains unclear. We found here that the activation of cytosolic RIG-I-like receptors (RLRs) resulted in the selective suppression of transcription of the gene encoding the p40 subunit of interleukin 12 (Il12b) that was effectively induced by the activation of Toll-like receptors (TLRs). The RLR-activated transcription factor IRF3 bound dominantly, relative to IRF5, to the Il12b promoter, where it interfered with the TLR-induced assembly of a productive transcription-factor complex. The activation of RLRs in mice attenuated TLR-induced responses of the T helper type 1 cell (TH1 cell) and interleukin 17–producing helper T cell (TH17 cell) subset types and, consequently, viral infection of mice caused death at sublethal doses of bacterial infection. The innate immune receptor cross-interference we describe may have implications for infection-associated clinical episodes.

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Figure 1: Cytokine-expression profiles after activation of PRRs.
Figure 2: Binding of IRF3 to the Il12b promoter after activation of RLRs.
Figure 3: IRF5-dependent induction of Il12b in IRF3-deficient cells after stimulation of RLRs.
Figure 4: RLR-activated IRF3 interferes with the TLR-activated productive transcription complex.
Figure 5: IRF3-mediated suppression of Il12b induction by RLR signaling.
Figure 6: T cell polarization induced by PRR signaling or microbial infection.
Figure 7: Suppression of Il12b induction and enhancement of susceptibility to bacteria by the virus-RLR-IRF3 axis.

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References

  1. Janeway, C.A. Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Steinman, R.M. & Hemmi, H. Dendritic cells: translating innate to adaptive immunity. Curr. Top. Microbiol. Immunol. 311, 17–58 (2006).

    CAS  PubMed  Google Scholar 

  3. Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Blasius, A.L. & Beutler, B. Intracellular toll-like receptors. Immunity 32, 305–315 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Marshak-Rothstein, A. & Rifkin, I.R. Immunologically active autoantigens: the role of toll-like receptors in the development of chronic inflammatory disease. Annu. Rev. Immunol. 25, 419–441 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Honda, K. & Taniguchi, T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 6, 644–658 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Tamura, T., Yanai, H., Savitsky, D. & Taniguchi, T. The IRF family transcription factors in immunity and oncogenesis. Annu. Rev. Immunol. 26, 535–584 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Nish, S. & Medzhitov, R. Host defense pathways: role of redundancy and compensation in infectious disease phenotypes. Immunity 34, 629–636 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bakaletz, L.O. Developing animal models for polymicrobial diseases. Nat. Rev. Microbiol. 2, 552–568 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Trinchieri, G. Type I interferon: friend or foe? J. Exp. Med. 207, 2053–2063 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Benveniste, E.N. & Qin, H. Type I interferons as anti-inflammatory mediators. Sci. STKE 2007, pe70 (2007).

    Article  PubMed  Google Scholar 

  14. Takaoka, A. et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature 434, 243–249 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Murphy, T.L. et al. Regulation of interleukin 12 p40 expression through an NF-κB half-site. Mol. Cell. Biol. 15, 5258–5267 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Plevy, S.E. et al. Multiple control elements mediate activation of the murine and human interleukin 12 p40 promoters: evidence of functional synergy between C/EBP and Rel proteins. Mol. Cell. Biol. 17, 4572–4588 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mori, M. et al. Identification of Ser-386 of interferon regulatory factor 3 as critical target for inducible phosphorylation that determines activation. J. Biol. Chem. 279, 9698–9702 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Panne, D., Maniatis, T. & Harrison, S.C. An atomic model of the interferon-β enhanceosome. Cell 129, 1111–1123 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Trinchieri, G. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat. Rev. Immunol. 3, 133–146 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Kastelein, R.A., Hunter, C.A. & Cua, D.J. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu. Rev. Immunol. 25, 221–242 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Murphy, K.M. et al. Signaling and transcription in T helper development. Annu. Rev. Immunol. 18, 451–494 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. O'Quinn, D.B., Palmer, M.T., Lee, Y.K. & Weaver, C.T. Emergence of the Th17 pathway and its role in host defense. Adv. Immunol. 99, 115–163 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Schnare, M. et al. Toll-like receptors control activation of adaptive immune responses. Nat. Immunol. 2, 947–950 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Ciavarra, R.P. et al. Impact of macrophage and dendritic cell subset elimination on antiviral immunity, viral clearance and production of type 1 interferon. Virology 342, 177–189 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Oxenius, A., Karrer, U., Zinkernagel, R.M. & Hengartner, H. IL-12 is not required for induction of type 1 cytokine responses in viral infections. J. Immunol. 162, 965–973 (1999).

    CAS  PubMed  Google Scholar 

  27. O'Connell, R.M. et al. Type I interferon production enhances susceptibility to Listeria monocytogenes infection. J. Exp. Med. 200, 437–445 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nguyen, H., Hiscott, J. & Pitha, P.M. The growing family of interferon regulatory factors. Cytokine Growth Factor Rev. 8, 293–312 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Yoboua, F. et al. Respiratory syncytial virus-mediated NF-(B p65 phosphorylation at serine 536 is dependent on RIG-I, TRAF6, and IKKβ. J. Virol. 84, 7267–7277 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Holt, P.G. & Sly, P.D. Interactions between RSV infection, asthma, and atopy: unraveling the complexities. J. Exp. Med. 196, 1271–1275 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Manel, N. et al. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 467, 214–217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chehimi, J. et al. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J. Exp. Med. 179, 1361–1366 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Vajdic, C.M. & Leeuwen, M.T. Cancer incidence and risk factors after solid organ transplantation. Int. J. Cancer 125, 1747–1754 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Banchereau, J. & Pascual, V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25, 383–392 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Nakajima, A. et al. Cell type-dependent proapoptotic role of Bcl2L12 revealed by a mutation concomitant with the disruption of the juxtaposed Irf3 gene. Proc. Natl. Acad. Sci. USA 106, 12448–12452 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Negishi, H. et al. Evidence for licensing of IFN-γ-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program. Proc. Natl. Acad. Sci. USA 103, 15136–15141 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Krieg, A.M. et al. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374, 546–549 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Choi, M.K. et al. A selective contribution of the RIG-I-like receptor pathway to type I interferon responses activated by cytosolic DNA. Proc. Natl. Acad. Sci. USA 106, 17870–17875 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Alexopoulou, L., Holt, A.C., Medzhitov, R. & Flavell, R.A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Diebold, S.S. et al. Viral infection switches non-plasmacytoid dendritic cells into high interferon producers. Nature 424, 324–328 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Hornung, V. et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science 314, 994–997 (2006).

    Article  PubMed  Google Scholar 

  42. Pichlmair, A. et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science 314, 997–1001 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Ishii, K.J. et al. A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat. Immunol. 7, 40–48 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Stetson, D.B. & Medzhitov, R. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24, 93–103 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Negishi, H. et al. Negative regulation of Toll-like-receptor signaling by IRF-4. Proc. Natl. Acad. Sci. USA 102, 15989–15994 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ivanov, I.I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank R. Medzhitov, A. Iwasaki, J. Ravetch, D. Savitsky and H. Rosen for advice; M. Kubo, M. Yoneyama, S. Nakae, S. Kano, F. Ohtake, H. Tani, N. Atarashi, M. Matsumoto, K. Nakayama and T. Negishi for discussions; and T. Ban, N. Endo, T. Kawaguchi, R. Takeda, M. Taniguchi and M. Shishido for technical assistance. Supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant-In-Aid for Scientific Research on Innovative Areas, Global Center of Excellence Program 'Integrative Life Science Based on the Study of Biosignaling Mechanisms'), the Japan Science and Technology Agency (Core Research for Evolutional Science and Technology) and the Japan Society for the Promotion of Science (A.N. and R.K.).

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  1. Hideo Negishi, Hideyuki Yanai and Akira Nakajima: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Immunology, Institute of Industrial Science, University of Tokyo, Tokyo, Japan

    Hideo Negishi, Hideyuki Yanai, Ryuji Koshiba, Atsushi Matsuda, Kosuke Matsuki, Shoji Miki, Junko Nishio & Tadatsugu Taniguchi

  2. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan

    Hideo Negishi, Hideyuki Yanai, Akira Nakajima, Ryuji Koshiba, Koji Atarashi, Atsushi Matsuda, Kosuke Matsuki, Shoji Miki, Junko Nishio, Kenya Honda & Tadatsugu Taniguchi

  3. Core Research for Evolution Science and Technology, Japan Science and Technology Agency, Tokyo, Japan

    Hideo Negishi, Hideyuki Yanai, Atsushi Matsuda, Junko Nishio & Tadatsugu Taniguchi

  4. Technology and Development Team for the BioSignal Program, Subteam for BioSignal Integration, RIKEN BioResource Center, Tsukuba, Japan

    Takahiro Doi

  5. Institute for Systems Biology, Seattle, Washington, USA

    Alan Aderem

  6. Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA

    Stephen T Smale

  7. Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan

    Koji Atarashi

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Contributions

H.N., H.Y., A.N., R.K., K.A. and K.H. designed, did and analyzed most of the experiments; A.N. and A.M. did ChIP assays; K.M., S.M. and J.N. did viral infection and RT-PCR experiments; A.A., T.D. and S.T.S. provided materials and advice for specific experiments; and T.T. provided overall coordination for the conception, design and supervision of the study and wrote the manuscript (with input from H.N., H.Y., A.N. and K.H.).

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Correspondence to Tadatsugu Taniguchi.

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Negishi, H., Yanai, H., Nakajima, A. et al. Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses. Nat Immunol 13, 659–666 (2012). https://doi.org/10.1038/ni.2307

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