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

Nature Immunology volume 16, pages 1060–1068 (2015)Cite this article

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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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Figure 1: LCs resist apoptosis after exposure to IR.
Figure 2: LCs rapidly repair IR-induced double strand breaks.
Figure 3: Overexpression of Cdkn1a and pro-survival genes by LCs.
Figure 4: Ontogenically distinct LCs differed in their sensitivity to IR.
Figure 5: Mediators up- and downstream of CDKN1A affect the sensitivity of LCs to IR.
Figure 6: Enhanced tumor growth in IR-treated mice.
Figure 7: Acute exposure to IR triggers the LC-mediated generation of Treg cells.

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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

  1. Juliana Idoyaga

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

  2. Jeremy G Price and Juliana Idoyaga: These authors contributed equally to this work.

Authors and 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.

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Correspondence to Miriam Merad.

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Integrated supplementary information

Supplementary Figure 1 LCs are resistant to sub-lethal (6 Gy) and lethal (12 Gy) doses of IR.

(a) CD45.1 mice were exposed to either 6 Gy (sub-lethal) or 12 Gy (lethal) IR. In the case of lethal irradiation, mice were injected with BM from CD45.2 mice to avoid IR-induced death. Kinetics of the absolute number of CD45.1 epidermal LC in the ears skin is shown relative to the absolute number of cells before irradiation. (b) Scatter plot of γ-H2AX in epidermal LCs as assessed by flow cytometry 24 h following exposure to either 6 Gy or 12 Gy IR-treatment. (c) Percentage of DNA damage measured by the COMET assay in skin epidermal LCs 24 h after by either 6 Gy and 12 Gy IR-treatment. For (a – b) data are pooled from two independent experiment, n=5 mice total. Data are shown as mean +/− SD. For (c) data are representative of 2 independent experiments with at least n=50 COMETs counted per experiment, and is shown as a whisker plot depicting the 10th, 50th, and 90th percentiles with outliers.

Supplementary Figure 2 Ccr7−/− LCs are a phenocopy of wild-type LCs in DNA-repair kinetics after exposure to IR.

(a) Representative bar graph of fold induction of γ-H2AX over baseline values in Ccr7−/− LCs. LC cell suspension were irradiated with 6 Gy and analyzed for γ-H2AX by flow cytometry 15 min and 2 h later. In the case of 24 h time-point, whole mice were irradiated and LCs subsequently harvested by enzymatic digestion for γ-H2AX analysis by flow cytometry. (b) Representative whisker plot of % DNA damage measured by COMET assay of Ccr7−/− LC isolated by flow cytometry 24 h after exposure to 6 Gy IR. (c) Bar graph shows the fold induction of γ-H2AX in epidermal LCs as assessed by flow cytometry 24 h following exposure to either 6 Gy IR-, UV- or Cisplatin- treatment. For (a & c) n=3 mice/group, data representative of 2 independent experiments and shown mean +/− SD. For (b) data are representative of 2 independent experiments with at least n=50 COMETs counted per experiment, and is shown as a whisker plot depicting the 10th, 50th, and 90th percentiles with outliers. *p<0.05, **p≤0.01 and ***p≤0.001.

Supplementary Figure 3 Cdkn1a expression in mutant mice and absence of DNA-repair defects in alternative pathways.

(a) WT, Cdkn1a−/−, Trp53−/− and Nfe2l2−/− mice were treated with 6 Gy IR. 24 h after irradiation, LCs were flow-purified from the skin and Cdkn1a levels were assessed by QPCR. Mean +/− SD of two experiments with a total of 4 mice is shown. (b) As in a, but CDKN1A protein levels were measured 48 h after IR by flow cytometry. Shown is a representative experiment of two, and numbers represent the MFI. (c) WT, Cdkn1a−/−, ATM−/− and Foxo3−/− mice were exposed to 6 Gy IR. 24 h after IR, expression of γ-H2AX was assessed by flow cytometry, and is expressed as the mean +/− SD fold-induction relative to the non-irradiated control (n= 4-8 mice in 2-3 different experiments). p values of <.05 are labeled as * and p≤0.01 are labeled as **.

Supplementary Figure 4 IR-treated mice are more susceptible to tumor growth shortly after irradiation.

(a) Mice were irradiated with 6 Gy followed 2 h later by the injection of 1x106 EL-4 tumor cells subcutaneously, and tumor volume was assessed at the indicated time points. (b) Bar graph of tumor (left) and tdLN (right) infiltrating Foxp3+ Treg cells as assessed 12 d after tumor challenge. (c) Mice were exposed to 6 Gy IR or left untreated. 12-24 h or 5 weeks after IR-treatment, mice were inoculated subcutaneously with 5×105 B16 melanoma cell line. Tumor volume was assessed at the indicated time points. (d) Tumor infiltrating (left) and tdLN (right) Foxp3+ Treg cells was evaluated 12 d after tumor challenge. In all cases, data show the mean +/− SD of 5-8 animals in 1-2 experiments. p values of ≤0.01 are labeled as ** and p≤0.001 as ***.

Supplementary Figure 5 LCs from chimeric mice lack CDKN1A but express DEC205.

(a) WT mice were treated with 12 Gy IR and transplanted with BM from Ly75−/− mice. Two months after BM transplantation, the expression of DEC205 was evaluated by flow cytometry. Representative gating strategy demonstrating that the only cells expressing DEC205 in the sdLN of BM chimeras are Epcam+CD11b+MHCII+ embryonic-derived LCs. The flow plot is pre-gated on all sdLN APCs (CD11c+MHCII+). (b) CD45.2 WT or Cdkn1a−/− mice were treated with 12 Gy IR and transplanted with BM from CD45.1 mice. LCs were analyzed 9-12 weeks after transplantation by flow cytometry for the expression of CD45.1 donor marker. (c) As in (b), but LCs were flow-purified and analyzed for the expression of Cdkn1a by QPCR. For (a, b) Data are representative of n=10 mice. For (c) data is representative of one of two independent experiments with 2-3 animals per group.

Supplementary Figure 6 MHC class II expression in LCs is required for the generation of Treg cells after IR treatment.

(a,b) Foxp3-DTR mice were exposed to 6 Gy IR followed by the subcutaneous inoculation of 5 x 105 B16 tumor cells 12 h later. 5 d after tumor challenge, and every 2 d thereafter, mice were inoculated with DT i.p. (a) Tumor volumes were assessed at the indicated time points. (b) Tumor infiltrating and tdLN Foxp3+ Treg cells were assessed 12 d after tumor challenge by flow cytometry. Shown is the mean +/− SD of 3 animals in one experiment. (c, d) H2−/− mice were lethally irradiated and reconstituted with BM cells isolated from either WT or Cdkn1a−/− mice. Two months post-transplantation, mice were further 6 Gy IR-treated and injected subcutaneously with 5 x 105 B16 melanoma cells 12 h later. (c) Graph depicting tumor volumes as the mean +/− SD of n=4 mice in two different experiments. (d) Tumor infiltrating Treg cells are shown as the percentage of total hematopoietic cells (gated as CD45+ cells) in B16 tumors at 14 d post-B16 injection. Data are pooled from two independent experiments, n≥2 mice per experiment. Data are plotted as Mean +/− SD. p values of ≤0.01 are labeled as ** and p≤0.001 as ***.

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Supplementary Table 1

List of antibodies for flow cytometry (PDF 98 kb)

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Price, J., Idoyaga, J., Salmon, H. et al. CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation. Nat Immunol 16, 1060–1068 (2015). https://doi.org/10.1038/ni.3270

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