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The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue–resident regulatory T cells

Nature Immunology volume 16, pages 276285 (2015) | Download Citation

  • An Erratum to this article was published on 21 April 2015

This article has been updated

Abstract

Foxp3+ regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.

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  • 08 April 2015

    In the version of this article initially published, the Acknowledgments section was incomplete. The correct text should begin "We thank P. O'Brien, M. Mochizuki and N. Takeno for assistance with tissue collection...." The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank P. O'Brien, M. Mochizuki and N. Takeno for assistance with tissue collection, S. Wada for animal care, M. Febbraio and A. Lew for critical advice, E. Cretney for mice and E. Bandala-Sanchez, V. Bryant and J. Brady for reagents. We are grateful to K. Nakanishi (Hyogo College of Medicine), T. Mak (The Campbell Family Institute for Breast Cancer Research), and U. Klein (Columbia University) for mice. Supported by the National Health and Medical Research Council of Australia (A.K., S.L.N. and G.K.S.), the Sylvia and Charles Viertel Foundation (A.K.), the Australian Research Council (A.K. and S.L.N.), the Diabetes Australia Research Trust (J.M.W.), PRESTO from the Japan Science and Technology Agency (K.M.), and a Grant-in Aid for Scientific Research (B) (26293110 to K.M.) and a Grant-in-Aid for Scientific Research (S) (22229004 to S. Koyasu) from the Japan Society for the Promotion of Science. W.L., P.L. and W.J.L. are supported by the Division of Intramural Research, National Heart, Blood, and Lung Institute, US National Institutes of Health. This study was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.

Author information

Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

    • Ajithkumar Vasanthakumar
    • , Annie Xin
    • , Yang Liao
    • , Renee Gloury
    • , Lisa A Mielke
    • , Shoukat Afshar-Sterle
    • , Seth L Masters
    • , John M Wentworth
    • , Gordon K Smyth
    • , Wei Shi
    • , Stephen L Nutt
    •  & Axel Kallies
  2. The Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.

    • Ajithkumar Vasanthakumar
    • , Annie Xin
    • , Yang Liao
    • , Renee Gloury
    • , Lisa A Mielke
    • , Shoukat Afshar-Sterle
    • , Seth L Masters
    • , John M Wentworth
    • , Stephen L Nutt
    •  & Axel Kallies
  3. Laboratory for Immune Cell Systems, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

    • Kazuyo Moro
    •  & Shigeo Koyasu
  4. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Tokyo, Japan.

    • Kazuyo Moro
    •  & Susumu Nakae
  5. Division of Immunobiology, Department of Medical Life Science, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Japan.

    • Kazuyo Moro
  6. Laboratory for Mucosal Immunity, RIKEN Research Center for Integrative Medical Sciences, Yokohama, Japan.

    • Shimpei Kawamoto
    •  & Sidonia Fagarasan
  7. Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

    • Susumu Nakae
  8. Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.

    • Hirohisa Saito
  9. Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Peng Li
    • , Wei Liao
    •  & Warren J Leonard
  10. Department of Computing and Information Systems, University of Melbourne, Parkville, Victoria, Australia.

    • Wei Shi
  11. The Department of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.

    • Gordon K Smyth
  12. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.

    • Shigeo Koyasu

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Contributions

A.V. planned and performed most experiments; K.M. performed experiments related to the IL-33 and ST2-deficient mice; A.X., S.A.-S., Y.L., P.L., W.L., W.S., W.J.L. and G.K.S. did or analyzed the RNA and ChIP sequencing experiments; S. Kawamoto and S.F. did the immunofluorescence; L.A.M. and R.G. performed additional experiments; S.N. and H.S. contributed reagents; S.L.M. and J.M.W. contributed to the scientific planning and organization of experiments; S.L.N. and S. Koyasu designed experiments; A.K. oversaw and designed the study; A.K. and A.V. wrote the manuscript.

Competing interests

S.K. is a consultant for Medical and Biological Laboratories (MBL).

Corresponding author

Correspondence to Axel Kallies.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–8, and Supplementary Tables 4 and 5

CSV files

  1. 1.

    Supplementary Table 1

    Top 200 DE genes_cTregs Vs eTregs

  2. 2.

    Supplementary Table 2

    DE genes encoding transcription factors_cTregs Vs eTregs

  3. 3.

    Supplementary Table 3

    DE genes involved in migration_cTregs Vs eTregs

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DOI

https://doi.org/10.1038/ni.3085

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