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IL-33 Induces Antigen-Specific IL-5⁺ T Cells and Promotes Allergic-Induced Airway Inflammation Independent of IL-4¹

Mariola Kurowska-Stolarska^*, Pete Kewin^*, Grace Murphy^*, Remo C. Russo, Bartosz Stolarski^*, Cristiana Couto Garcia, Mousa Komai-Koma^*, Nick Pitman^*, Yubin Li^*, Andrew N. J. McKenzie, Mauro M. Teixeira, Foo Y. Liew^2,* and Damo Xu^2,*

^* Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow United Kingdom; Departamento de Bioquimica e Imunologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Pampulha, Brazil; and Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom

Type 2 cytokines (IL-4, IL-5, and IL-13) play a pivotal role in helminthic infection and allergic disorders. CD4⁺ T cells which produce type 2 cytokines can be generated via IL-4-dependent and -independent pathways. Although the IL-4-dependent pathway is well documented, factors that drive IL-4-independent Th2 cell differentiation remain obscure. We report here that the new cytokine IL-33, in the presence of Ag, polarizes murine and human naive CD4⁺ T cells into a population of T cells which produce mainly IL-5 but not IL-4. This polarization requires IL-1R-related molecule and MyD88 but not IL-4 or STAT6. The IL-33-induced T cell differentiation is also dependent on the phosphorylation of MAPKs and NF-B but not the induction of GATA3 or T-bet. In vivo, ST2^–/– mice developed attenuated airway inflammation and IL-5 production in a murine model of asthma. Conversely, IL-33 administration induced the IL-5-producing T cells and exacerbated allergen-induced airway inflammation in wild-type as well as IL-4^–/– mice. Finally, adoptive transfer of IL-33-polarized IL-5⁺IL-4^–T cells triggered airway inflammation in naive IL-4^–/– mice. Thus, we demonstrate here that, in the presence of Ag, IL-33 induces IL-5-producing T cells and promotes airway inflammation independent of IL-4.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study received financial support from the Medical Research Council U.K., the Wellcome Trust, and the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil.

² Address correspondence and reprint requests to Dr. Foo Y. Liew and Dr. Damo Xu, Division of Immunology, Infection and Inflammation, 120 University Place, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow G12 8TA, United Kingdom. E-mail addresses: f.y.liew{at}clinmed.gla.ac.uk and d.xu{at}clinmed.gla.ac.uk

³ Abbreviations used in this paper: ST2, IL-1R-related molecule; IL-1RAcP, IL-1 receptor accessory protein; BAL, bronchoalveolar lavage; DLN, draining lymph node; EPO, eosinophil peroxidase; WT, wild type; i.n., intranasal(ly); PAS, periodic acid-Schiff; iNKT, invariant NKT; TRIF, Toll/IL-1R domain-containing adaptor inducing IFN-β.

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