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The Development of Airway Hyperreactivity in T-bet-Deficient Mice Requires CD1d-Restricted NKT Cells¹

Hye Young Kim^*, Muriel Pichavant^*, Ponpan Matangkasombut^*,, Youngil I. Koh^*, Paul B. Savage, Rosemarie H. DeKruyff^* and Dale T. Umetsu^2,*

^* Division of Immunology and Allergy, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602

T-bet^–/– mice have been shown to have a profound deficiency in the ability to generate invariant NKT (iNKT) cells in the periphery due to a halt in terminal maturation, but despite this deficiency, T-bet^–/– mice develop spontaneous airway hyperreactivity (AHR) and airway inflammation. Because in some situations the development of AHR requires the presence of iNKT cells, we sought to more clearly understand how AHR develops in T-bet^–/– mice by examining T-bet^–/– mice in several distinct mouse models of asthma, including spontaneous, OVA-induced and -galactosylceramide (-GalCer)-induced AHR. Surprisingly, we found that administration of -GalCer, which very specifically activates iNKT cells, greatly increased the AHR response in the T-bet^–/– mice. Moreover, in T-bet^–/– mice, spontaneous AHR as well as AHR induced with OVA or -GalCer were all eliminated by blocking CD1d, the restricting element of iNKT cells, using an anti-CD1d-blocking mAb. Although the number of the iNKT cells in T-bet^–/– mice was reduced compared with that in wild-type mice, the remaining iNKT cells produced primarily IL-4 and IL-13, and only minimal amounts of IFN-. We conclude therefore that the AHR that develops in T-bet^–/– mice is dependent on the presence of iNKT cells, and that whereas T-bet^–/– have reduced numbers of iNKT cells, these are sufficient for the development of AHR.

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 Grants HL062348 and AI26322 from the National Institutes of Health and funds from the Bunning Food Allergy Project.

² Address correspondence and reprint requests to Dr. Dale T. Umetsu, Division of Immunology and Allergy, Children’s Hospital Boston, Karp Laboratories, Room 10127, One Blackfan Circle, Boston, MA 02115. E-mail address: dale.umetsu{at}childrens.harvard.edu

³ Abbreviations used in this paper: AHR, airway hyperreactivity; -GalCer, -galactosylceramide; BAL, bronchoalveolar lavage; iNKT, invariant NKT; WT, wild type.

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