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CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation

Nature Immunology volume 16, pages 10601068 (2015) | Download Citation

Abstract

Treatment with ionizing radiation (IR) can lead to the accumulation of tumor-infiltrating regulatory T cells (Treg cells) and subsequent resistance of tumors to radiotherapy. Here we focused on the contribution of the epidermal mononuclear phagocytes Langerhans cells (LCs) to this phenomenon because of their ability to resist depletion by high-dose IR. We found that LCs resisted apoptosis and rapidly repaired DNA damage after exposure to IR. In particular, we found that the cyclin-dependent kinase inhibitor CDKN1A (p21) was overexpressed in LCs and that Cdkn1a−/− LCs underwent apoptosis and accumulated DNA damage following IR treatment. Wild-type LCs upregulated major histocompatibility complex class II molecules, migrated to the draining lymph nodes and induced an increase in Treg cell numbers upon exposure to IR, but Cdkn1a−/− LCs did not. Our findings suggest a means for manipulating the resistance of LCs to IR to enhance the response of cutaneous tumors to radiotherapy.

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Acknowledgements

We thank J. Manfredi and S. Aronson (Icahn School of Medicine at Mount Sinai) for Trp53−/− mice; P. Heeger (Icahn School of Medicine at Mount Sinai) for FoxP3-DTR mice; M.C. Nussenzweig (The Rockefeller University) for Ly75−/− mice; S. Ghaffari (Icahn School of Medicine at Mount Sinai) for Foxo3−/− mice; C. Rivera for help in maintaining mouse colonies; R. Bagnell (University of North Carolina) for the Image-J CometScore module; A. Nussenzweig for input on the manuscript; the Flow Cytometry, Microscopy, and Irradiator Shared Resource Facilities of the Icahn School of Medicine at Mount Sinai for contributions; and the Immunological Genome Project Consortium for resources. Supported by the US National Institutes of Health (T32 CA078207-14 and T32 GM007280 to J.G.P.), the American Medical Association (J.G.P.), the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the US National Institutes of Health (R00 AR062595 to J.I.) and the National Cancer Institute of the US National Institutes of Health (R01 CA173861 and R01 CA154947 to M.M.).

Author information

Author notes

    • Juliana Idoyaga

    Present address: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.

    • Jeremy G Price
    •  & Juliana Idoyaga

    These authors contributed equally to this work.

Affiliations

  1. Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Jeremy G Price
    • , Juliana Idoyaga
    • , Hélène Salmon
    • , Brandon Hogstad
    • , Saghi Ghaffari
    • , Marylene Leboeuf
    •  & Miriam Merad
  2. Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Jeremy G Price
    • , Juliana Idoyaga
    • , Hélène Salmon
    • , Brandon Hogstad
    • , Marylene Leboeuf
    •  & Miriam Merad
  3. Laboratory of Cellular Physiology and Immunology and Chris Browne Center for Immunology and Immune Diseases, The Rockefeller University, New York, New York, USA.

    • Juliana Idoyaga
  4. Department of Developmental & Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Carolina L Bigarella
    •  & Saghi Ghaffari
  5. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Saghi Ghaffari
  6. Department of Medicine, Division of Hematology, Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Saghi Ghaffari

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Contributions

J.G.P., J.I. and M.M. contributed to the design of and discussions of the work; J.G.P. and J.I. performed experiments, analyzed data and prepared the figures; H.S. contributed to in vivo tumor experiments; B.H. contributed to RT-PCR experiments; C.L.B. and S.G. developed protocols for the comet assay and provided Foxo3−/− mice; M.L. contributed to the maintenance of animal colonies and generation of BM chimeras; J.G.P., J.I. and M.M. wrote the manuscript; and all authors edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Miriam Merad.

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    Supplementary Table 1

    List of antibodies for flow cytometry

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DOI

https://doi.org/10.1038/ni.3270

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