Abstract

Group 2 innate lymphoid cells (ILC2s) and CD4+ type 2 helper T cells (TH2 cells) are defined by their similar effector cytokines, which together mediate the features of allergic immunity. We found that tissue ILC2s and TH2 cells differentiated independently but shared overlapping effector function programs that were mediated by exposure to the tissue-derived cytokines interleukin 25 (IL-25), IL-33 and thymic stromal lymphopoietin (TSLP). Loss of these three tissue signals did not affect lymph node priming, but abrogated the terminal differentiation of effector TH2 cells and adaptive lung inflammation in a T cell–intrinsic manner. Our findings suggest a mechanism by which diverse perturbations can activate type 2 immunity and reveal a shared local-tissue-elicited checkpoint that can be exploited to control both innate and adaptive allergic inflammation.

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Acknowledgements

We thank M. Ji, K. Davis, M. Consengco and Z. Wang for technical expertise, A. Barczak and R. Barbeau for assistance with RNA-Seq, A. McKenzie, S. Akira, S. Ziegler and the US National Institutes of Health Tetramer Core Facility for reagents, and A. Abbas and M. Ansel for comments on the manuscript. Supported by the US National Institutes of Health (AI026918, AI030663, HL107202, HL128903, K08AI113143 and DP5-OD12178), the Howard Hughes Medical Institute and the Sandler Asthma Basic Research Center at the University of California San Francisco.

Author information

Author notes

    • Steven J Van Dyken
    •  & Jesse C Nussbaum

    These authors contributed equally to this work.

Affiliations

  1. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Steven J Van Dyken
    • , Jesse C Nussbaum
    • , Jinwoo Lee
    • , Hong-Erh Liang
    • , Joshua L Pollack
    • , Genevieve E Haliburton
    • , Alexander Marson
    • , David J Erle
    •  & Richard M Locksley
  2. Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Ari B Molofsky
  3. Lung Biology Center, University of California, San Francisco, San Francisco, California, USA.

    • Joshua L Pollack
    •  & David J Erle
  4. Department of Epidemiology and Biostatistics, Institute for Human Genetics, University of California, San Francisco, San Francisco, California, USA.

    • Rachel E Gate
    •  & Chun J Ye
  5. Diabetes Center, University of California, San Francisco, San Francisco, California, USA.

    • Genevieve E Haliburton
    •  & Alexander Marson
  6. Innovative Genomics Initiative (IGI), University of California, Berkeley, Berkeley, California, USA.

    • Alexander Marson
  7. UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

    • Alexander Marson
    •  & Richard M Locksley
  8. Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California, USA.

    • Richard M Locksley

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Contributions

J.C.N. and S.J.V.D. performed experiments, interpreted data and wrote the manuscript. J.L., A.B.M. and G.E.H. provided experimental assistance. H.-E.L. generated reporter mouse strains. J.L.P. analyzed the RNA-Seq data. R.E.G. analyzed the ATAC-Seq data. D.J.E., A.M., C.J.Y. and R.M.L. directed the studies, and R.M.L. wrote the paper with J.C.N. and S.J.V.D.

Competing interests

A.M. is a scientific advisor for and has licensed technology to Juno Therapeutics. The Marson laboratory has sponsored research collaborations with Epinomics and Juno Therapeutics.

Corresponding author

Correspondence to Richard M Locksley.

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DOI

https://doi.org/10.1038/ni.3582

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