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Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells

Abstract

Type 2 immunity is critical for defense against cutaneous infections but also underlies the development of allergic skin diseases. We report the identification in normal mouse dermis of an abundant, phenotypically unique group 2 innate lymphoid cell (ILC2) subset that depended on interleukin 7 (IL-7) and constitutively produced IL-13. Intravital multiphoton microscopy showed that dermal ILC2 cells specifically interacted with mast cells, whose function was suppressed by IL-13. Treatment of mice deficient in recombination-activating gene 1 (Rag1−/−) with IL-2 resulted in the population expansion of activated, IL-5-producing dermal ILC2 cells, which led to spontaneous dermatitis characterized by eosinophil infiltrates and activated mast cells. Our data show that ILC2 cells have both pro- and anti-inflammatory properties and identify a previously unknown interactive pathway between two innate populations of cells of the immune system linked to type 2 immunity and allergic diseases.

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Figure 1: Identification and phenotype of dermal ILC2 cells.
Figure 2: Development and homeostatic requirements of dILC2 cells.
Figure 3: IL-13 production by dILC2 cells in the steady state.
Figure 4: Visualization of dILC2 cells in vivo.
Figure 5: Interaction of dILC2 cells with skin-resident mast cells.
Figure 6: IL-2-induced activation and proliferation of ILC2 cells in vivo.
Figure 7: IL-2 stimulation of dILC2 cells in vivo.

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Acknowledgements

We thank J. Ho Cho and J. Sprent (Garvan Institute) for mice deficient in IL-7, IL-15 or Jak3; M. Kleinschek (DNAX) for Il25−/− mice; P. Besmer (Sloan Kettering Institute) for c-Kit–eGFP mice; Z. Eshar (Weizmann Institute of Science) for mouse SPE-7 hybridoma cells that produce IgE monoclonal antibody specific for 2,4-dinitrophenyl; A. Smith, S. Allen, S. Dervish, C. Zhu, A. Terry, Y. Wen Loh, K. Price and M. Camberis for technical assistance; M. Rizk and J. Qin for animal husbandry; L. Feigenbaum for help in preparing mice with transgenic expression of a bacterial artificial chromosome; N. Kolesnikoff and H. Taing for help with culturing bone marrow–derived mast cells; and L. Cavanagh for administrative assistance. Supported by the Australian National Health and Medical Research Council (M.A.G.), the Health Research Council of New Zealand, the Marjorie Barclay Trust, the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases (US National Institutes of Health) and the Cancer Institute New South Wales (W.W.).

Author information

Authors and Affiliations

Authors

Contributions

B.R., W.W. and G.LG. conceived of the idea for this project and wrote the paper; B.R., R.K. and N.S. did immunology and flow cytometry experiments; M.A.G. provided expertise in mast-cell biology and, together with K.H.Y., did mast cell–stimulation experiments; B.R., R.J. and P.L.T. designed and did imaging experiments; E.F.-B., A.J.M., S.S.T., T.V.G., H.A.B., B.S.K., D.A. and B.F.d.S.G. contributed to experimental design and did experiments; X.C. and W.E.P. generated the 4C13R mice; and all authors discussed the results and commented on the paper.

Corresponding authors

Correspondence to Graham Le Gros or Wolfgang Weninger.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 (PDF 1574 kb)

Supplementary Video 1

Representative video of mixed chimeric mouse skin (described in Fig. 4d) by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. Blood vessels were visualized using Evans blue (red). Extracellular matrix in the dermis was detected by second harmonic generation (SHG) signals (blue). Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 5). (MOV 655 kb)

Supplementary Video 2

Representative video of mixed chimeric mouse skin (described in Fig. 4d) by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. SHG signals shown in blue. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 5). (MOV 770 kb)

Supplementary Video 3

Representative video of mixed chimeric mouse skin (described in Fig. 4d) by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. mTomato+ cells shown in red. Blood vessels were visualized using Evans blue (white). SHG signals shown in blue. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 5). (MOV 3543 kb)

Supplementary Video 4

Representative video of mixed chimeric mouse skin (described in Fig. 4d) by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. mTomato+ cells shown in red. SHG signals shown in blue. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 5). (MOV 1452 kb)

Supplementary Video 5

Representative video of albino C57BL/6 mice 8 weeks after irradiation and co-transfer of bone marrow from Rag1−/− Cxcr6+/gfp, mG/mT and CD11c-eYFP mice, as imaged by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. eYFP+ dermal dendritic cell show in yellow. mTomato+ cells shown in red. Blood vessels were visualized using Evans blue (white). SHG signals shown in blue. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 4). (MOV 1268 kb)

Supplementary Video 6

Representative video of Brainbow32 mouse skin by intravital multiphoton microscopy. RFP fluorescence has been pseudocoloured such that RFPhi cells appear yellow while RFPdim cells are red. Blood vessels were visualized using Evans blue (white). Right: Close up of migratory RFPdim cells. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 3 independent experiments (n = 3). (MOV 3649 kb)

Supplementary Video 7

Representative video of BrainbowAA Cxcr6+/gfp mouse skin by intravital multiphoton microscopy. RFPhi mast cells shown in red. eGFP+ cells shown in green. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 2). (MOV 843 kb)

Supplementary Video 8

[Representative video of mixed chimeric mouse skin (described in Fig. 5e) by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. RFPhi mast cells shown in red. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 4). (MOV 334 kb)

Supplementary Video 9

Representative video of mixed chimeric mouse skin (described in Fig. 5e) by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. RFPhi mast cells shown in red. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 4). (MOV 487 kb)

Supplementary Video 10

Representative video of mixed chimeric mouse skin (described in Fig. 5e) by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. RFPhi mast cells shown in red. Boxes indicate dILC2 that remained in close proximity with mast cells throughout the observation period. Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 4). (MOV 488 kb)

Supplementary Video 11

Representative video of IL-2-treated Rag1−/− Cxcr6+/gfp mice (described in Fig. 7b) by intravital multiphoton microscopy. eGFP+ dILC2 shown in green. Blood vessels were visualized using Evans blue (red). Extracellular matrix in the dermis was detected by SHG signals (blue). Video represents a z-projection through a volume of 28 μm within the dermis. Time shown in mm:ss. Data are representative of 2 independent experiments (n = 2). (MOV 1963 kb)

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Roediger, B., Kyle, R., Yip, K. et al. Cutaneous immunosurveillance and regulation of inflammation by group 2 innate lymphoid cells. Nat Immunol 14, 564–573 (2013). https://doi.org/10.1038/ni.2584

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