title: The IL-33 receptor (ST2) regulates early IL-13 production in fungus-induced allergic airway inflammation.
abstract: Allergic airway inflammation (AAI) in response to environmental antigens is an increasing medical problem, especially in the Western world. Type 2 interleukins (IL) are central in the pathological response but their importance and cellular source(s) often rely on the particular allergen. Here, we highlight the cellular sources and regulation of the prototypic type 2 cytokine, IL-13, during the establishment of AAI in a fungal infection model using Cryptococcus neoformans. IL-13 reporter mice revealed a rapid onset of IL-13 competence within innate lymphoid cells type 2 (ILC2) and IL-33R(+) T helper (Th) cells. ILC2 showed IL-33-dependent proliferation upon infection and significant IL-13 production. Th cells essentially required IL-33 to become either GATA3(+) or GATA3(+)/Foxp3(+) hybrids. GATA3(+) Th cells almost exclusively contributed to IL-13 production but hybrid GATA3(+)/Foxp3(+) Th cells did not. In addition, alveolar macrophages upregulated the IL-33R and subsequently acquired a phenotype of alternative activation (Ym1(+), FIZZ1(+), and arginase-1(+)) linked to type 2 immunity. Absence of adaptive immunity in rag2(-/-) mice resulted in attenuated AAI, revealing the need for Th2 cells for full AAI development. Taken together, in pulmonary cryptococcosis ILC2 and GATA3(+) Th2 cells produce early IL-13 largely IL-33R-dependent, thereby promoting goblet cell metaplasia, pulmonary eosinophilia, and alternative activation of alveolar macrophages.
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Piehler
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Eschke
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schulze
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Protschka
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Müller
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Grahnert
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Richter
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Heyen
authors.affiliation: Institute of Pathology, Klinikum Fulda gAG, Fulda, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Köhler
authors.affiliation: International Center for Genetic Engineering and Biotechnology, Cape Town Component & SAMRC, UCT, IDM, Division of Immunology, Cape Town, South Africa.
authors.forename: F
authors.initials: F
authors.lastname: Brombacher
authors.affiliation: Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Alber
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003453:Cryptococcosis / Q000276:immunology*; D003455:Cryptococcus neoformans / Q000276:immunology*; D005260:Female; D050990:GATA3 Transcription Factor / Q000378:metabolism; D006967:Hypersensitivity / Q000276:immunology*; D007113:Immunity, Innate; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology* / Q000382:microbiology; D008262:Macrophage Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology* / Q000382:microbiology
chemical_list: D000485:Allergens; D000946:Antigens, Fungal; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D018123:Receptors, Interleukin