title: Enforced expression of Gata3 in T cells and group 2 innate lymphoid cells increases susceptibility to allergic airway inflammation in mice.
abstract: Airway inflammation in allergic asthma reflects a threshold response of the innate immune system, including group 2 innate lymphoid cells (ILC2), followed by an adaptive Th2 cell-mediated response. Transcription factor Gata3 is essential for differentiation of both Th2 cells and ILC2. We investigated the effects of enforced Gata3 expression in T cells and ILC2 on the susceptibility of mice to allergic airway inflammation (AAI). We used CD2-Gata3 transgenic (Tg) mice with enforced Gata3 expression driven by the CD2 promoter, which is active both in T cells and during ILC2 development. CD2-Gata3 Tg mice and wild-type (WT) littermates were analyzed in mild models of AAI without adjuvants. Whereas OVA allergen exposure did not induce inflammation in WT controls, CD2-Gata3 Tg mice showed clear AAI and enhanced levels of IL-5 and IL-13 in bronchoalveolar lavage. Likewise, in house dust mite-driven asthma, CD2-Gata3 Tg mice were significantly more susceptible to AAI than WT littermates, whereby both ILC2 and Th2 cells were important cellular sources of IL-5 and IL-13 in bronchoalveolar lavage and lung tissue. Compared with WT littermates, CD2-Gata3 Tg mice contained increased numbers of ILC2, which expressed high levels of IL-33R and contributed significantly to early production of IL-4, IL-5, and IL-13. CD2-Gata3 Tg mice also had a unique population of IL-33-responsive non-B/non-T lymphoid cells expressing IFN-γ. Enforced Gata3 expression is therefore sufficient to enhance Th2 and ILC2 activity, and leads to increased susceptibility to AAI after mild exposure to inhaled harmless Ags that otherwise induce Ag tolerance.
authors.affiliation: Department of Pulmonary Medicine, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands;
authors.forename: Alex
authors.initials: A
authors.lastname: KleinJan
authors.forename: Roel G J
authors.initials: RG
authors.lastname: Klein Wolterink
authors.forename: Yelvi
authors.initials: Y
authors.lastname: Levani
authors.forename: Marjolein J W
authors.initials: MJ
authors.lastname: de Bruijn
authors.forename: Henk C
authors.initials: HC
authors.lastname: Hoogsteden
authors.forename: Menno
authors.initials: M
authors.lastname: van Nimwegen
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D018801:CD2 Antigens / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13 / Q000096:biosynthesis / Q000378:metabolism; D015847:Interleukin-4 / Q000096:biosynthesis / Q000378:metabolism; D015848:Interleukin-5 / Q000096:biosynthesis / Q000378:metabolism; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin; D011401:Promoter Regions, Genetic; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018801:CD2 Antigens; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D018793:Interleukin-13; D015848:Interleukin-5; D018123:Receptors, Interleukin; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin