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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bieber, T. Atopic dermatitis. N. Engl. J. Med. 358, 1483–1494 (2008).
Li, M. et al. Induction of thymic stromal lymphopoietin expression in keratinocytes is necessary for generating an atopic dermatitis upon application of the active vitamin D3 analogue MC903 on mouse skin. J. Invest. Dermatol. 129, 498–502 (2009).
Spits, H. et al. Innate lymphoid cells—a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).
Chang, Y.J. et al. Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity. Nat. Immunol. 12, 631–638 (2011).
Mjösberg, J.M. et al. Human IL-25- and IL-33-responsive type 2 innate lymphoid cells are defined by expression of CRTH2 and CD161. Nat. Immunol. 12, 1055–1062 (2011).
Monticelli, L.A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Price, A.E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. USA 107, 11489–11494 (2010).
Wong, S.H. et al. Transcription factor RORα is critical for nuocyte development. Nat. Immunol. 13, 229–236 (2012).
Minty, A. et al. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature 362, 248–250 (1993).
Cohn, L. et al. Th2-induced airway mucus production is dependent on IL-4Rα, but not on eosinophils. J. Immunol. 162, 6178–6183 (1999).
Grünig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).
Pope, S.M. et al. IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism. J. Allergy Clin. Immunol. 108, 594–601 (2001).
Wilhelm, C. et al. An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat. Immunol. 12, 1071–1077 (2011).
Faulkner, H., Humphreys, N., Renauld, J.C., Van Snick, J. & Grencis, R. Interleukin-9 is involved in host protective immunity to intestinal nematode infection. Eur. J. Immunol. 27, 2536–2540 (1997).
Richard, M., Grencis, R.K., Humphreys, N.E., Renauld, J.C. & Van Snick, J. Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice. Proc. Natl. Acad. Sci. USA 97, 767–772 (2000).
Shimbara, A. et al. IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J. Allergy Clin. Immunol. 105, 108–115 (2000).
Sumaria, N. et al. Cutaneous immunosurveillance by self-renewing dermal γδ T cells. J. Exp. Med. 208, 505–518 (2011).
Georgopoulos, K. et al. The Ikaros gene is required for the development of all lymphoid lineages. Cell 79, 143–156 (1994).
Kirstetter, P., Thomas, M., Dierich, A., Kastner, P. & Chan, S. Ikaros is critical for B cell differentiation and function. Eur. J. Immunol. 32, 720–730 (2002).
Muzumdar, M.D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007).
Thomis, D.C., Gurniak, C.B., Tivol, E., Sharpe, A.H. & Berg, L.J. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270, 794–797 (1995).
Barlow, J.L. et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J. Allergy Clin. Immunol. 129, 191–198 (2012).
Hu-Li, J. et al. Regulation of expression of IL-4 alleles: analysis using a chimeric GFP/IL-4 gene. Immunity 14, 1–11 (2001).
Mjösberg, J. et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity 37, 649–659 (2012).
Li, M. et al. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc. Natl. Acad. Sci. USA 103, 11736–11741 (2006).
Unutmaz, D. et al. The primate lentiviral receptor Bonzo/STRL33 is coordinately regulated with CCR5 and its expression pattern is conserved between human and mouse. J. Immunol. 165, 3284–3292 (2000).
Possot, C. et al. Notch signaling is necessary for adult, but not fetal, development of RORγt+ innate lymphoid cells. Nat. Immunol. 12, 949–958 (2011).
Ng, L.G. et al. Migratory dermal dendritic cells act as rapid sensors of protozoan parasites. PLoS Pathog. 4, e1000222 (2008).
Hepworth, M.R. et al. Mast cells orchestrate type 2 immunity to helminths through regulation of tissue-derived cytokines. Proc. Natl. Acad. Sci. USA 109, 6644–6649 (2012).
Livet, J. et al. Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450, 56–62 (2007).
Berrozpe, G. et al. A distant upstream locus control region is critical for expression of the Kit receptor gene in mast cells. Mol. Cell Biol. 26, 5850–5860 (2006).
Grimbaldeston, M.A. et al. Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am. J. Pathol. 167, 835–848 (2005).
Biggs, L. et al. Evidence that vitamin D3 promotes mast cell-dependent reduction of chronic UVB-induced skin pathology in mice. J. Exp. Med. 207, 455–463 (2010).
Halim, T.Y., Krauss, R.H., Sun, A.C. & Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).
Boyman, O., Kovar, M., Rubinstein, M.P., Surh, C.D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924–1927 (2006).
Hoyler, T. et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634–648 (2012).
Hamid, Q. et al. In vivo expression of IL-12 and IL-13 in atopic dermatitis. J. Allergy Clin. Immunol. 98, 225–231 (1996).
Zheng, T. et al. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J. Invest. Dermatol. 129, 742–751 (2009).
Ranson, T. et al. IL-15 is an essential mediator of peripheral NK-cell homeostasis. Blood 101, 4887–4893 (2003).
Malek, T.R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).
Wolf, A.I. et al. Plasmacytoid dendritic cells are dispensable during primary influenza virus infection. J. Immunol. 182, 871–879 (2009).
von Freeden-Jeffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).
Kennedy, M.K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771–780 (2000).
Kleinschek, M.A. et al. IL-25 regulates Th17 function in autoimmune inflammation. J. Exp. Med. 204, 161–170 (2007).
Herbst, T. et al. Antibodies and IL-3 support helminth-induced basophil expansion. Proc. Natl. Acad. Sci. USA 109, 14954–14959 (2012).
Al-Shami, A. et al. A role for thymic stromal lymphopoietin in CD4+ T cell development. J. Exp. Med. 200, 159–168 (2004).
Roediger, B., Ng, L.G., Smith, A.L., Fazekas de St Groth, B. & Weninger, W. Visualizing dendritic cell migration within the skin. Histochem. Cell Biol. 130, 1131–1146 (2008).
Mitchell, A.J. et al. Technical advance: autofluorescence as a tool for myeloid cell analysis. J. Leukoc. Biol. 88, 597–603 (2010).
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
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
Ethics declarations
Competing interests
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.2584
This article is cited by
-
Slow integrin-dependent migration organizes networks of tissue-resident mast cells
Nature Immunology (2023)
-
Immunological characteristics of CD103+CD8+ Tc cells in the liver of C57BL/6 mouse infected with plasmodium NSM
Parasitology Research (2023)
-
Dietary antigens suppress the proliferation of type 2 innate lymphoid cells by restraining homeostatic IL-25 production
Scientific Reports (2022)
-
Context-dependent function of TSLP and IL-1β in skin allergic sensitization and atopic march
Nature Communications (2022)
-
Dengue virus co-opts innate type 2 pathways to escape early control of viral replication
Communications Biology (2022)