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The development of inflammatory TH-17 cells requires interferon-regulatory factor 4

Nature Immunology volume 8, pages 958–966 (2007)Cite this article

Abstract

Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper type 2 cells. Here we show that IRF4 is also critical for the generation of interleukin 17–producing T helper cells (TH-17 cells), which are associated with experimental autoimmune encephalomyelitis. IRF4-deficient (Irf4−/−) mice did not develop experimental autoimmune encephalomyelitis, and T helper cells from such mice failed to differentiate into TH-17 cells. Transfer of wild-type T helper cells into Irf4−/− mice rendered the mice susceptible to experimental autoimmune encephalomyelitis. Irf4−/− T helper cells had less expression of RORγt and more expression of Foxp3, transcription factors important for the differentiation of TH-17 and regulatory T cells, respectively. Altered regulation of both transcription factors contributed to the phenotype of Irf4−/− T helper cells. Our data position IRF4 at the center of T helper cell development, influencing not only T helper type 2 but also TH-17 differentiation.

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Figure 1: Irf4−/− T helper cells do not differentiate into TH-17 cells in vitro.
Figure 2: IRF4-specific siRNA blocks TH-17 differentiation of wild-type (Irf4+/+) cells.
Figure 3: Irf4−/− mice are protected from EAE.
Figure 4: A differentiation defect intrinsic to T helper cells mediates the EAE resistance of Irf4−/− mice.
Figure 5: Relationship between IRF4 and RORγt expression.
Figure 6: Relationship between IRF4 and Foxp3 expression.

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References

  1. Harrington, L.E. et al. Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    Article  CAS  Google Scholar 

  2. Infante-Duarte, C., Horton, H.F., Byrne, M.C. & Kamradt, T. Microbial lipopeptides induce the production of IL-17 in TH cells. J. Immunol. 165, 6107–6115 (2000).

    Article  CAS  Google Scholar 

  3. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    Article  CAS  Google Scholar 

  4. Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    Article  CAS  Google Scholar 

  5. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  Google Scholar 

  6. Mangan, P.R. et al. Transforming growth factor-β induces development of the TH17 lineage. Nature 441, 231–234 (2006).

    Article  CAS  Google Scholar 

  7. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    Article  CAS  Google Scholar 

  8. Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. TH17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).

    Article  CAS  Google Scholar 

  9. Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  Google Scholar 

  10. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–488 (2007).

    Article  CAS  Google Scholar 

  11. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. advance online publication, 20 June 2007 (doi:10.1038/ni1488).

  12. Honda, K., Takaoka, A. & Taniguchi, T. Type I interferon gene induction by the interferon regulatory factor family of transcription factors 6. Immunity 25, 349–360 (2006).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Lohoff, M. & Mak, T.W. Roles of interferon-regulatory factors in T-helper-cell differentiation. Nat. Rev. Immunol. 5, 125–135 (2005).

    Article  CAS  Google Scholar 

  15. Giese, N.A. et al. Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J. Exp. Med. 186, 1535–1546 (1997).

    Article  CAS  Google Scholar 

  16. 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  Google Scholar 

  17. Lohoff, M. et al. Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells. J. Exp. Med. 192, 325–336 (2000).

    Article  CAS  Google Scholar 

  18. Scharton, K.T., Contursi, C., Masumi, A., Sher, A. & Ozato, K. Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction. J. Exp. Med. 186, 1523–1534 (1997).

    Article  Google Scholar 

  19. Taki, S. et al. Multistage regulation of TH1-type immune responses by the transcription factor IRF-1. Immunity 6, 673–679 (1997).

    Article  CAS  Google Scholar 

  20. Hu, C.M., Jang, S.Y., Fanzo, J.C. & Pernis, A.B. Modulation of T cell cytokine production by interferon regulatory factor-4. J. Biol. Chem. 277, 49238–49246 (2002).

    Article  CAS  Google Scholar 

  21. Lohoff, M. et al. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc. Natl. Acad. Sci. USA 99, 11808–11812 (2002).

    Article  CAS  Google Scholar 

  22. Rengarajan, J. et al. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J. Exp. Med. 195, 1003–1012 (2002).

    Article  CAS  Google Scholar 

  23. Lohoff, M. et al. Enhanced TCR-induced apoptosis in interferon regulatory factor 4-deficient CD4+ Th cells. J. Exp. Med. 200, 247–253 (2004).

    Article  CAS  Google Scholar 

  24. Liang, S.C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by TH17 cells and cooperatively enhance expression of antimicrobial peptides 1. J. Exp. Med. 203, 2271–2279 (2006).

    Article  CAS  Google Scholar 

  25. Nogai, A. et al. Lipopolysaccharide injection induces relapses of experimental autoimmune encephalomyelitis in nontransgenic mice via bystander activation of autoreactive CD4+ cells. J. Immunol. 175, 959–966 (2005).

    Article  CAS  Google Scholar 

  26. Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  Google Scholar 

  27. Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).

    Article  CAS  Google Scholar 

  28. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  Google Scholar 

  29. Yang, X.O. et al. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells 1. J. Biol. Chem. 282, 9358–9363 (2007).

    Article  CAS  Google Scholar 

  30. Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells 1. PLoS Biol. 5, e38 (2007).

    Article  Google Scholar 

  31. Mantel, P.Y. et al. Molecular mechanisms underlying FOXP3 induction in human T cells 1. J. Immunol. 176, 3593–3602 (2006).

    Article  CAS  Google Scholar 

  32. Zorn, E. et al. IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571–1579 (2006).

    Article  CAS  Google Scholar 

  33. Brass, A.L., Kehrli, E., Eisenbeis, C.F., Storb, U. & Singh, H. Pip, a lymphoid-restricted IRF, contains a regulatory domain that is important for autoinhibition and ternary complex formation with the Ets factor PU.1. Genes Dev. 10, 2335–2347 (1996).

    Article  CAS  Google Scholar 

  34. Gupta, S., Jiang, M., Anthony, A. & Pernis, A.B. Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4. J. Exp. Med. 190, 1837–1848 (1999).

    Article  CAS  Google Scholar 

  35. Diehl, S. et al. Inhibition of TH1 differentiation by IL-6 is mediated by SOCS1. Immunity 13, 805–815 (2000).

    Article  CAS  Google Scholar 

  36. Rincon, M., Anguita, J., Nakamura, T., Fikrig, E. & Flavell, R.A. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J. Exp. Med. 185, 461–469 (1997).

    Article  CAS  Google Scholar 

  37. Nessler, S. et al. Suppression of autoimmune encephalomyelitis by a neurokinin-1 receptor antagonist–a putative role for substance P in CNS inflammation. J. Neuroimmunol. 179, 1–8 (2006).

    Article  CAS  Google Scholar 

  38. Grogan, J.L. et al. Cross-reactivity of myelin basic protein-specific T cells with multiple microbial peptides: experimental autoimmune encephalomyelitis induction in TCR transgenic mice. J. Immunol. 163, 3764–3770 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank D. Littman for RORγt-expressing retrovirus; A. Scheffold (Deutsches Rheuma-Forschungszentrum Berlin) for help with siRNA experiments; R. Volkmer (Institut für Medizinische Immunologie, Charité-Universitätsmedizin Berlin) MOG peptide; P. Sack for technical assistance; and M. Saunders for scientific editing. Supported by the Deutsche Forschungsgemeinschaft (LO 396, TR SFB 6044 and GRK 767 to M.L.) and the Gemeinnützige Hertie-Stiftung (1.319.110/03/03 to T.K.).

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Authors and Affiliations

  1. Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Marburg, 35043, Germany

    Anne Brüstle, Magdalena Huber, Christine Rosenplänter & Michael Lohoff

  2. Institut für Immunologie, Universitätsklinikum Jena, Jena, 07740, Germany

    Sylvia Heink & Thomas Kamradt

  3. Institut für Neuropathologie, Universität Göttingen, Göttingen, 37075, Germany

    Christine Stadelmann

  4. Institut für Immunologie, Marburg, 35043, Germany

    Philipp Yu

  5. Advanced Medical Discovery Institute, University of Toronto, Toronto, M5G2C1, Ontario, Canada

    Enrico Arpaia & Tak W Mak

  6. Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, M5G2C1, Ontario, Canada

    Tak W Mak

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  1. Anne Brüstle
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Contributions

A.B. did the in vitro experiments with assistance from M.H.,C.R., P.Y. and E.A.; S.H. did the in vivo and ex vivo experiments; C.S. did the histology; and T.W.M.,T.K. and M.L. provided advice and overall direction and supervised project planning and execution.

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Correspondence to Michael Lohoff.

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The authors declare no competing financial interests.

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Supplementary Figures 1–4, Tables 1 and 2, and Methods (PDF 971 kb)

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Brüstle, A., Heink, S., Huber, M. et al. The development of inflammatory TH-17 cells requires interferon-regulatory factor 4. Nat Immunol 8, 958–966 (2007). https://doi.org/10.1038/ni1500

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