Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1

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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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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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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.

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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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