@article{e96311855f5b4fb1a54cb8d0d0d26575,
title = "CDKN1A regulates Langerhans cell survival and promotes T reg cell generation upon exposure to ionizing irradiation",
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.",
author = "Price, {Jeremy G.} and Juliana Idoyaga and H{\'e}l{\`e}ne Salmon and Brandon Hogstad and Bigarella, {Carolina L.} and Saghi Ghaffari and Marylene Leboeuf and Miriam Merad",
note = "Funding Information: 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.). Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",
year = "2015",
month = oct,
day = "21",
doi = "10.1038/ni.3270",
language = "English",
volume = "16",
pages = "1060--1068",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "10",
}