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Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1

Nature Immunology volume 14, pages 12291236 (2013) | Download Citation

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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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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.

Author information

Author notes

    • Harinder Singh

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

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.

Competing interests

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.

Corresponding authors

Correspondence to Chauncey J Spooner or Harinder Singh.

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DOI

https://doi.org/10.1038/ni.2743