title: IL-2 is a critical regulator of group 2 innate lymphoid cell function during pulmonary inflammation.
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.
  
  
  CONCLUSIONS
  Innate cell-derived IL-2 is a critical cofactor in regulating ILC2 function in pulmonary type 2 pathology.
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address: b.roediger@centenary.org.au.
authors.forename: Ben
authors.initials: B
authors.lastname: Roediger
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kyle
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Szun S
authors.initials: SS
authors.lastname: Tay
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mitchell
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Bolton
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Guy
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Sioh-Yang
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Forbes-Blom
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia; Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, Australia.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Tong
authors.affiliation: Maurice Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin (UVCM), University of Bern, Bern, Switzerland.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Köller
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Elena
authors.initials: E
authors.lastname: Shklovskaya
authors.affiliation: Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Ill; Department of Thoracic and Cardiovascular Surgery, Loyola University Chicago, Maywood, Ill.
authors.forename: Makio
authors.initials: M
authors.lastname: Iwashima
authors.affiliation: Maurice Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin (UVCM), University of Bern, Bern, Switzerland.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand; Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Graham
authors.initials: G
authors.lastname: Le Gros
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address: b.fazekas@centenary.org.au.
authors.forename: Barbara
authors.initials: B
authors.lastname: Fazekas de St Groth
authors.affiliation: Centenary Institute, Newtown, Australia; Discipline of Dermatology, Sydney Medical School, University of Sydney, Sydney, Australia; Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, Australia. Electronic address: w.weninger@centenary.org.au.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D007113:Immunity, Innate / Q000276:immunology; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000097:blood / Q000276:immunology*; D011657:Pulmonary Eosinophilia / Q000097:blood / Q000276:immunology*; D013154:Spleen / Q000276:immunology
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007376:Interleukin-2; C499308:Rag2 protein, mouse; C064658:RAG-1 protein
keywords: Group 2 innate lymphoid cells; IL-13; IL-2; eosinophilic crystalline pneumonia; pulmonary inflammation