IL-2 is a critical regulator of group 2 innate lymphoid cell function during pulmonary inflammation - 04/12/15
, Ryan Kyle, BSc c, Szun S. Tay, PhD a, b, Andrew J. Mitchell, PhD a, b, Holly A. Bolton, PhD a, b, Thomas V. Guy, BSc a, b, Sioh-Yang Tan, PhD a, b, Elizabeth Forbes-Blom, PhD c, Philip L. Tong, MD a, b, d, Yasmin Köller, MSc e, Elena Shklovskaya, MD, PhD a, b, Makio Iwashima, PhD f, g, Kathy D. McCoy, PhD e, Graham Le Gros, PhD c, h, Barbara Fazekas de St Groth, MD, PhD a, b, ⁎, ∗, ‡ , Wolfgang Weninger, MD a, b, d, ⁎, ∗, ‡ Abstract |
Background |
Group 2 innate lymphoid cells (ILC2) have been implicated in the pathogenesis of allergic lung diseases. However, the upstream signals that regulate ILC2 function during pulmonary inflammation remain poorly understood. ILC2s have been shown to respond to exogenous IL-2, but the importance of endogenous IL-2 in ILC2 function in vivo remains unclear.
Objective |
We sought to understand the role of IL-2 in the regulation of ILC2 function in the lung.
Methods |
We used histology, flow cytometry, immunohistochemistry, ELISA, and quantitative PCR with knockout and reporter mice to dissect pulmonary ILC2 function in vivo. We examined the role of ILC2s in eosinophilic crystalline pneumonia, an idiopathic type 2 inflammatory lung condition of mice, and the effect of IL-2 deficiency on this disease. We determined the effect of IL-2 administration on pulmonary ILC2 numbers and function in mice in the steady state and after challenge with IL-33.
Results |
We discovered an unexpected role for innate cell–derived IL-2 as a major cofactor of ILC2 function during pulmonary inflammation. Specifically, we found that IL-2 was essential for the development of eosinophilic crystalline pneumonia, a type 2 disease characterized by increased numbers of activated ILC2s. We show that IL-2 signaling serves 2 distinct functions in lung ILC2s, namely promoting cell survival/proliferation and serving as a cofactor for the production of type 2 cytokines. We further demonstrate that group 3 innate lymphoid cells are an innate immune source of IL-2 in the lung.
Conclusion |
Innate cell–derived IL-2 is a critical cofactor in regulating ILC2 function in pulmonary type 2 pathology.
Le texte complet de cet article est disponible en PDF.Key words : Group 2 innate lymphoid cells, IL-2, eosinophilic crystalline pneumonia, IL-13, pulmonary inflammation
Abbreviations used : DAPI, ECP, Foxp3, FUCCI, GFP, ILC, ILC2, ILC3, JES6-1, MHCII, NF-κB, qPCR, RAG, STAT5, TCR, TLR2, YFP
Plan
| Supported by grants 1030145 and 1047041 (to W.W.) and 1012524 and 1051854 (to B.F.d.S.G.) from the National Health and Medical Research Council of Australia, the Health Research Council of New Zealand (G.L.G.), the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP/2007-2013) and ERC grant agreement 281785, and the Swiss National Science Foundation (K.D.M.). W.W. is supported by a fellowship from the Cancer Institute New South Wales and B.F.d.S.G. by a fellowship from the National Health and Medical Research Council of Australia. |
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| Disclosure of potential conflict of interest: B. Roediger has received research support from the National Health Medical Research Council and Sydney University, is employed by Centenary Institute, and has received travel support from the Japanese Society for Investigative Dermatology and the Austrian Academy of Sciences. R. Kyle has received research support from the Health Research Council of New Zealand, is employed by Malaghan Institute of Medical Research, and has received travel support from the National Institutes of Health. S. S. Tay has received research support from the National Health Medical Research Council and is employed by Centenary Institute. A. J. Mitchell has received research support from the National Health Medical Research Council and the National Foundation for Medical Research and Innovation and is employed by Centenary Institute. H. A. Bolton has received research support from the National Health Medical Research Council and is employed by Centenary Institute. T. V. Guy has received research support from the National Health Medical Research Council. S.-Y. Tan has received research support from the National Health Medical Research Council and Sydney University and is employed by Centenary Institute. E. Forbes-Blom has received research support from the Health Research Council of New Zealand, the Ministry of Business, Innovation, and Employment, and Olympic Biotec and is employed by Malaghan Institute of Medical Research. P. L. Tong has consultant arrangements with Griffith University, has received research support from LEO Foundation Grant, has received payment for development of educational presentations from AusDoc Seminar Series, and has received travel support from AbbVie. Y. Köller and K. D. McCoy have received research support from the European Research Council. E. Shklovskaya has received research support from the National Health Medical Research Council and Cancer Council NSW and is employed by Centenary Institute. M. Iwashima is employed by Loyola University Chicago and has received research support from the National Institutes of Health. G. Le Gros has received research support from the Health Research Council of New Zealand and is employed by Malaghan Institute of Medical Research. B. Fazekas de St Groth has received research support from the National Health Medical Research Council, the Cancer Council NSW, Cancer Institute NSW, Ramaciotti Foundation, the Australian Research Council, the National Institutes of Health–BAA, and Cure Cancer; has consultant arrangements with Queensland University of Technology and the National Health Medical Research Council; is employed by Centenary Institute; has provided expert testimony for the Medical Research Commercialization Fund; has received royalties from Becton Dickinson; and has received travel support from the Australasian Society for Immunology, the International Conference on Systems Biology, the International Congress of Immunology, the Transplantation Society of Australia and New Zealand, and Griffith University. W. Weninger has received research support from the National Health Medical Research Council, has consultant arrangements with AbbVie, is employed by University of Sydney, and receives payment for lectures from AbbVie. |
Vol 136 - N° 6
P. 1653 - décembre 2015 Retour au numéro
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