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Induction of Airway Hyperreactivity by IL-25 Is Dependent on a Subset of Invariant NKT Cells Expressing IL-17RB ¹

Philippe Stock^*, Vincent Lombardi, Viola Kohlrautz^* and Omid Akbari^2,

^* Department of Pediatric Pneumology and Immunology, University Hospital Charité, Berlin, Germany; and Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033

IL-25 has been shown to induce Th2 responses and airway hyperreactivity (AHR) in mice, but the mechanism of action is not understood and it is unclear which cells mediate this disease. In this study we show that the receptor for IL-25, IL-17RB, is highly expressed on a subset of naive and activated CD4⁺ invariant NKT (iNKT) cells, but not on activated T cells. IL-17RB⁺ iNKT cells produced large amounts of Th2 cytokines that were substantially increased by IL-25 stimulation. Furthermore, IL-17RB⁺ iNKT cells were capable of restoring AHR in iNKT cell-deficient mice, whereas IL-17RB^– iNKT cells failed to reconstitute AHR and lung inflammation. Finally, IL-17RB⁺ iNKT cells were detected in the lungs of wild-type mice, and induction of AHR by intranasal administration of IL-25 was significantly impaired in iNKT cell-deficient mice. Overall, our data suggest a critical role for iNKT cells in IL-25-mediated AHR. These results may lead to novel therapeutic approaches to target IL-17RB⁺ iNKT cells for the treatment of allergic asthma.

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 work was supported by National Institutes of Health Grant R01 AI066020 (to O.A.) and by German Research Foundation (DFG) Grant STO 467/4-2 (to P.S.).

² Address correspondence and reprint requests to Dr. Omid Akbari, University of Southern California, Keck School of Medicine, Department of Molecular Microbiology and Immunology, Norris Research Tower 5505, 1450 Biggy Street, Los Angeles, CA 90033-9605, E-mail address: akbari{at}usc.edu

³ Abbreviations used in this paper: AHR, airway hyperreactivity; BAL, bronchoalveolar lavage; BMDC, bone marrow-derived dendritic cell; DN, double negative; -GalCer, -galactosylceramide; i.n., intranasal(ly); iNKT, invariant NKT; Penh, enhanced pause; WT, wild type.