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Epigenetic and transcriptional signatures of stable versus plastic differentiation of proinflammatory γδ T cell subsets

Nature Immunology volume 14, pages 10931100 (2013) | Download Citation

Abstract

Two distinct subsets of γδ T cells that produce interleukin 17 (IL-17) (CD27 γδ T cells) or interferon-γ (IFN-γ) (CD27+ γδ T cells) develop in the mouse thymus, but the molecular determinants of their functional potential in the periphery remain unknown. Here we conducted a genome-wide characterization of the methylation patterns of histone H3, along with analysis of mRNA encoding transcription factors, to identify the regulatory networks of peripheral IFN-γ-producing or IL-17-producing γδ T cell subsets in vivo. We found that CD27+ γδ T cells were committed to the expression of Ifng but not Il17, whereas CD27 γδ T cells displayed permissive chromatin configurations at loci encoding both cytokines and their regulatory transcription factors and differentiated into cells that produced both IL-17 and IFN-γ in a tumor microenvironment.

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Acknowledgements

We thank V. Benes for technical assistance with the ChIP-seq experiments; J. Ribot, S. de Almeida and N. Gonçalves-Sousa for technical advice; H. Kulbe, F. Balkwill and R. Thompson for help with the ID8 tumor model; M.J. Nunes and E. Rodrigues for help with ChIP procedures; and M. Soares, A. Vieira and S. Marques for help with cell sorting; A. Hayday, L. Lefrançois and M. Saraiva for discussions; B. Arnold and C. Niehrs (Deutsches Krebsforschungszentrum, Heidelberg) for Dkk3-deficient mice; C. Terhorst and B. van Driel (Harvard Medical School) for Slamf1-deficient mice; K. Roby (University of Kansas) for ID8 ovarian cancer cells; A. Pamplona (Instituto de Medicina Molecular) for Plasmodium berghei ANKA with transgenic expression of GFP; P. Simas (Instituto de Medicina Molecular) for murid herpes virus 4; M. Correia-Neves (Universidade do Minho) for Mycobacterium avium strain 244.; C. Reis e Sousa (The London Research Institute) for Candida albicans yeast strain WT-SC 3314; and the staff of the animal and flow cytometry facilities of our institutes for experimental assistance. Supported by the European Research Council (StG_260352 to B.S.-S.), the Wellcome Trust (D.J.P.), the European Molecular Biology Organization (B.S.-S.), Fundação para a Ciência e Tecnologia (K.S., A.R.G. and M.R.) and the Graduate Program in Areas of Basic and Applied Biology of Universidade do Porto (M.R.).

Author information

Author notes

    • Nina Schmolka
    •  & Karine Serre

    These authors contributed equally to this work.

Affiliations

  1. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

    • Nina Schmolka
    • , Karine Serre
    • , Ana R Grosso
    • , Margarida Rei
    • , Anita Q Gomes
    •  & Bruno Silva-Santos
  2. Blizard Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.

    • Margarida Rei
    •  & Daniel J Pennington
  3. Escola Superior de Tecnologia da Saúde de Lisboa, Lisbon, Portugal.

    • Anita Q Gomes
  4. Instituto Gulbenkian de Ciência, Oeiras, Portugal.

    • Bruno Silva-Santos

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Contributions

N.S. planned and did experiments in Figures 1, 2, 4 and 5; K.S. planned and did experiments in Figures 3,4,5,6; A.R.G. planned and did experiments in Figures 1 and 2; M.R. planned and did experiments in Figure 6; A.Q.G. planned and did experiments in Figures 4 and 5; D.J.P. contributed to designing the study and writing the manuscript; A.Q.G. helped to design and supervise the study; and B.S.-S. designed and supervised the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Anita Q Gomes or Bruno Silva-Santos.

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DOI

https://doi.org/10.1038/ni.2702

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