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Direct control of regulatory T cells by keratinocytes

Nature Immunology volume 18, pages 334343 (2017) | Download Citation

Abstract

Environmental challenges to epithelial cells trigger gene expression changes that elicit context-appropriate immune responses. We found that the chromatin remodeler Mi-2β controls epidermal homeostasis by regulating the genes involved in keratinocyte and immune-cell activation to maintain an inactive state. Mi-2β depletion resulted in rapid deployment of both a pro-inflammatory and an immunosuppressive response in the skin. A key target of Mi-2β in keratinocytes is the pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP). Loss of TSLP receptor (TSLPR) signaling specifically in regulatory T (Treg) cells prevented their activation and permitted rapid progression from a skin pro-inflammatory response to a lethal systemic condition. Thus, in addition to their well-characterized role in pro-inflammatory responses, keratinocytes also directly support immune-suppressive responses that are critical for re-establishing organismal homeostasis.

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Acknowledgements

We thank P. Chambon (Institute of Genetics and Cellular and Molecular Biology) and V.K. Kuchroo (Brigham and Women's Hospital) for the Krt14-Cre-ERT2 mice and Foxp3-IRES-EGFP mice, respectively. We thank M.E. Bigby for consultation on lymphocyte isolation from the skin and L.M. Francisco and A.H. Sharpe for consultation on Treg cell and DC analysis. We thank E. Wu and B. Czyzewski for mouse husbandry, A. Cho, M. Ahl, J.E. King and J. Brandollni for bone marrow transplantation, and T. Minegishi for R platform support. We also thank J.M. Park, H. Cantor, H.J. Kim, F. Gounari and K. Khashayarsha for critical comments on the manuscript. This research was supported by NIH R21 AR055813, RO1 AR064390 and R01AR069132 to K.G., NIH RO1 AI068731 and PO1 HL098067 to S.F.Z., and NIH R01 AR055256 to B.A.M. K.G. is an MGH scholar supported by J. de Gunzburg. J.H. was supported by a Shiseido grant. High-throughput RNA sequencing was performed at the Bauer Center for Genomic research Harvard University, Cambridge.

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Affiliations

  1. Cuteneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.

    • Mariko Kashiwagi
    • , Junichi Hosoi
    • , Bruce A Morgan
    •  & Katia Georgopoulos
  2. Immunology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.

    • Jen-Feng Lai
    •  & Steven F Ziegler
  3. Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York, USA.

    • Janice Brissette

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Contributions

M.K. designed and performed experiments and analyzed experimental data. J.H. designed and executed cytokine studies on primary cultured keratinocytes and advised on DC and DETC studies. J.-F.L. provided experimental materials and advised on immunological studies. J.B. advised on keratinocyte transcriptional studies. S.F.Z. provided experimental materials and guidance throughout the project. K.G and B.A.M supervised research and analyzed data. M.K., K.G. and B.A.M wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mariko Kashiwagi or Katia Georgopoulos.

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https://doi.org/10.1038/ni.3661

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