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Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1

Nature Immunology volume 14, pages 1229–1236 (2013)Cite this article

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Abstract

Type 2 innate lymphoid cells (ILC2 cells) participate in host defense against helminth parasites and in allergic inflammation. Given their functional relatedness to type 2 helper T cells (TH2 cells), we explored whether Gfi1 acts as a shared transcriptional determinant in ILC2 cells. Gfi1 promoted the development of ILC2 cells and controlled their responsiveness during infection with Nippostrongylus brasiliensis and protease allergen–induced lung inflammation. Gfi1 'preferentially' regulated the responsiveness of ILC2 cells to interleukin 33 (IL-33) by directly activating Il1rl1, which encodes the IL-33 receptor (ST2). Loss of Gfi1 in activated ILC2 cells resulted in impaired expression of the transcription factor GATA-3 and a dysregulated genome-wide effector state characterized by coexpression of IL-13 and IL-17. Our findings establish Gfi1 as a shared determinant that reciprocally regulates the type 2 and IL-17 effector states in cells of the innate and adaptive immune systems.

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Figure 1: Gfi1 regulates the development of ILC2 cells.
Figure 2: Gfi1 regulates the activation of ILC2 cells during infection with N. brasiliensis.
Figure 3: Elicitation of ILC2 cells by papain challenge is impaired in the lungs of Gfi1−/− mice.
Figure 4: Gfi1 expression is correlated with the responsiveness of ILC2 cells to IL-33.
Figure 5: Gfi1 is required for the responsiveness of ILC2 cells to IL-33.
Figure 6: Loss of Gfi1 in ILC2 cells results in a hybrid effector state.
Figure 7: Gfi1 targets and regulates genes encoding components of the type 2 and IL-17 expression programs.

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References

  1. Spits, H. & Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30, 647–675 (2012).

    Article  CAS  Google Scholar 

  2. Zeng, H., Yucel, R., Kosan, C., Klein-Hitpass, L. & Moroy, T. Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells. EMBO J. 23, 4116–4125 (2004).

    Article  CAS  Google Scholar 

  3. Hock, H. et al. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431, 1002–1007 (2004).

    Article  CAS  Google Scholar 

  4. Karsunky, H. et al. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nat. Genet. 30, 295–300 (2002).

    Article  Google Scholar 

  5. Hock, H. et al. Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity 18, 109–120 (2003).

    Article  CAS  Google Scholar 

  6. Laslo, P. et al. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126, 755–766 (2006).

    Article  CAS  Google Scholar 

  7. Spooner, C.J., Cheng, J.X., Pujadas, E., Laslo, P. & Singh, H. A recurrent network involving the transcription factors PU.1 and Gfi1 orchestrates innate and adaptive immune cell fates. Immunity 31, 576–586 (2009).

    Article  CAS  Google Scholar 

  8. Yücel, R., Karsunky, H., Klein-Hitpass, L. & Moroy, T. The transcriptional repressor Gfi1 affects development of early, uncommitted c-Kit+ T cell progenitors and CD4/CD8 lineage decision in the thymus. J. Exp. Med. 197, 831–844 (2003).

    Article  Google Scholar 

  9. Zhu, J., Jankovic, D., Grinberg, A., Guo, L. & Paul, W.E. Gfi-1 plays an important role in IL-2-mediated Th2 cell expansion. Proc. Natl. Acad. Sci. USA 103, 18214–18219 (2006).

    Article  CAS  Google Scholar 

  10. Zhu, J. et al. Down-regulation of Gfi-1 expression by TGF-β is important for differentiation of Th17 and CD103+ inducible regulatory T cells. J. Exp. Med. 206, 329–341 (2009).

    Article  CAS  Google Scholar 

  11. Wong, S.H. et al. Transcription factor RORα is critical for nuocyte development. Nat. Immunol. 13, 229–236 (2012).

    Article  CAS  Google Scholar 

  12. Yang, Q., Saenz, S.A., Zlotoff, D.A., Artis, D. & Bhandoola, A. Cutting edge: Natural helper cells derive from lymphoid progenitors. J. Immunol. 187, 5505–5509 (2011).

    Article  CAS  Google Scholar 

  13. Yücel, R., Kosan, C., Heyd, F. & Moroy, T. Gfi1:green fluorescent protein knock-in mutant reveals differential expression and autoregulation of the growth factor independence 1 (Gfi1) gene during lymphocyte development. J. Biol. Chem. 279, 40906–40917 (2004).

    Article  Google Scholar 

  14. Hoyler, T. et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634–648 (2012).

    Article  CAS  Google Scholar 

  15. Price, A.E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. USA 107, 11489–11494 (2010).

    Article  CAS  Google Scholar 

  16. Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).

    Article  CAS  Google Scholar 

  17. Fallon, P.G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006).

    Article  CAS  Google Scholar 

  18. Voehringer, D., Reese, T.A., Huang, X., Shinkai, K. & Locksley, R.M. Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system. J. Exp. Med. 203, 1435–1446 (2006).

    Article  CAS  Google Scholar 

  19. Shroyer, N.F., Wallis, D., Venken, K.J., Bellen, H.J. & Zoghbi, H.Y. Gfi1 functions downstream of Math1 to control intestinal secretory cell subtype allocation and differentiation. Genes Dev. 19, 2412–2417 (2005).

    Article  CAS  Google Scholar 

  20. Halim, T.Y., Krauss, R.H., Sun, A.C. & Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).

    Article  CAS  Google Scholar 

  21. Yasuda, K. et al. Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice. Proc. Natl. Acad. Sci. USA 109, 3451–3456 (2012).

    Article  CAS  Google Scholar 

  22. Kim, B.S. et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci. Transl. Med. 5, 170ra116 (2013).

    Article  Google Scholar 

  23. Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).

    Article  CAS  Google Scholar 

  24. Smith, D.E. The biological paths of IL-1 family members IL-18 and IL-33. J. Leukoc. Biol. 89, 383–392 (2011).

    Article  CAS  Google Scholar 

  25. Shinnakasu, R. et al. Gfi1-mediated stabilization of GATA3 protein is required for Th2 cell differentiation. J. Biol. Chem. 283, 28216–28225 (2008).

    Article  CAS  Google Scholar 

  26. Zhu, J. et al. Growth factor independent-1 induced by IL-4 regulates Th2 cell proliferation. Immunity 16, 733–744 (2002).

    Article  CAS  Google Scholar 

  27. Duan, Z. & Horwitz, M. Targets of the transcriptional repressor oncoprotein Gfi-1. Proc. Natl. Acad. Sci. USA 100, 5932–5937 (2003).

    Article  CAS  Google Scholar 

  28. Malhotra, N. et al. A network of high-mobility group box transcription factors programs innate interleukin-17 production. Immunity 38, 681–693 (2013).

    CAS  PubMed  Google Scholar 

  29. Duan, Z., Zarebski, A., Montoya-Durango, D., Grimes, H.L. & Horwitz, M. Gfi1 coordinates epigenetic repression of p21Cip/WAF1 by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1. Mol. Cell Biol. 25, 10338–10351 (2005).

    Article  CAS  Google Scholar 

  30. Lehnertz, B. et al. Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function. J. Exp. Med. 207, 915–922 (2010).

    Article  CAS  Google Scholar 

  31. Allan, R.S. et al. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature 487, 249–253 (2012).

    Article  CAS  Google Scholar 

  32. Doe, C. et al. Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD. Chest 138, 1140–1147 (2010).

    Article  CAS  Google Scholar 

  33. Wang, Y.H. et al. A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J. Exp. Med. 207, 2479–2491 (2010).

    Article  CAS  Google Scholar 

  34. Cosmi, L. et al. Identification of a novel subset of human circulating memory CD4+ T cells that produce both IL-17A and IL-4. J. Allergy Clin. Immunol. 125, 222–230, e221–224 (2010).

    Article  CAS  Google Scholar 

  35. Walker, J.A., Barlow, J.L. & McKenzie, A.N. Innate lymphoid cells–how did we miss them? Nat. Rev. Immunol. 13, 75–87 (2013).

    Article  CAS  Google Scholar 

  36. Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011).

    Article  CAS  Google Scholar 

  37. Glasmacher, E. et al. A genomic regulatory element that directs assembly and function of immune-specific AP-1-IRF complexes. Science 338, 975–980 (2012).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank members of the Singh laboratory, as well as H. Xi, M. van Lookeren Campagne, D. Holmes, S. Lutz and W. Ouyang, for discussions; and the Mouse Genetics Department, FACS, microarray, DNA sequencing, microscopy, and oligonucleotide synthesis facilities at Genentech for assistance and reagents.

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  1. Harinder Singh

    Present address: Present address: Division of Immunobiology and the Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,

Authors and Affiliations

  1. Department of Discovery Immunology, Genentech, South San Francisco, California, USA

    Chauncey J Spooner, Vladimir Ramirez-Carrozzi, Rajita Pappu & Harinder Singh

  2. Translational Immunology, Genentech, South San Francisco, California, USA

    Justin Lesch, Donghong Yan, Meijuan Zhou, Wyne P Lee, Min Xu & Jason DeVoss

  3. Institute for Systems and Genomics Biology and Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA

    Aly A Khan

  4. Department of Bioinformatics, Genentech, South San Francisco, California, USA

    Alex Abbas

  5. Department of Molecular Biology, Genentech, South San Francisco, California, USA

    Robert Soriano & Zora Modrusan

  6. Center for Advanced Light Microscopy, Genentech, South San Francisco, California, USA

    Jeffrey Eastham-Anderson

  7. Department of Pathology, Genentech, South San Francisco, California, USA

    Lauri Diehl

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Contributions

C.J.S. and H.S. designed and interpreted the experiments and wrote the manuscript; C.J.S., D.Y. and M.X. used the N. brasiliensis infection model; C.J.S., J.L., and J.D. did the experiments with administration of IL-25 and IL-33; C.J.S, M.Z. and W.P.L. used the papain lung-inflammation model; J.E.-A. and L.D. assisted with the animal pathology; V.R.-C. and R.P. assisted with the in vitro ILC2 cell cultures; R.S. and Z.M. did the microarray analysis; and A.A. and A.A.K. did the computational and statistical analysis of the microarray and ChIP-seq data, respectively.

Corresponding authors

Correspondence to Chauncey J Spooner or Harinder Singh.

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C.J.S., J.L., D.Y., A.A., V.R.-C., M.Z., R.S., J.E.-A., L.D., W.P.L., Z.M., R.P., M.X. and J.D. are employees of Genentech.

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Spooner, C., Lesch, J., Yan, D. et al. Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1. Nat Immunol 14, 1229–1236 (2013). https://doi.org/10.1038/ni.2743

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