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iNKT Cells Require CCR4 to Localize to the Airways and to Induce Airway Hyperreactivity¹

Everett H. Meyer^*,, Marc-André Wurbel^,,¶, Tracy L. Staton, Muriel Pichavant^*, Matthew J. Kan^*, Paul B. Savage^||, Rosemarie H. DeKruyff^*,, Eugene C. Butcher^2,,#, James J. Campbell^2,,,¶ and Dale T. Umetsu^2,3,*,

^* Division of Immunology, Karp Laboratories, Children’s Hospital and Department of Pathology and Department of Dermatology, Harvard Medical School, Boston, MA 02115; Immunology Program and School of Medicine, Stanford University, Stanford, CA 94305; ^¶ Department of Dermatology, Brigham and Women’s Hospital, Boston, MA 02115; ^|| Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602; and ^# Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305

iNKT cells are required for the induction of airway hyperreactivity (AHR), a cardinal feature of asthma, but how iNKT cells traffic to the lungs to induce AHR has not been previously studied. Using several models of asthma, we demonstrated that iNKT cells required the chemokine receptor CCR4 for pulmonary localization and for the induction of AHR. In both allergen-induced and glycolipid-induced models of AHR, wild-type but not CCR4^–/– mice developed AHR. Furthermore, adoptive transfer of wild-type but not CCR4^–/– iNKT cells reconstituted AHR in iNKT cell-deficient mice. Moreover, we specifically tracked CCR4^–/– vs wild-type iNKT cells in CCR4^–/–:wild-type mixed BM chimeric mice in the resting state, and when AHR was induced by protein allergen or glycolipid. Using this unique model, we showed that both iNKT cells and conventional T cells required CCR4 for competitive localization into the bronchoalveolar lavage/airways compartment. These results establish for the first time that the pulmonary localization of iNKT cells critical for the induction of AHR requires CCR4 expression by iNKT cells.

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 These studies were supported by National Institutes of Health Grants 2R01AI046784-07A1 (to J.J.C.), R01 HL62348 (to D.T.U.), and R01 AI26322 (to D.T.U.). M.A.W. was supported by the Crohn’s and Colitis Foundation of America Research Fellowship (New York, NY).

² E.C.B., J.J.C., and D.T.U contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Dale T. Umetsu, Division of Immunology, Karp Laboratories, Children’s Hospital, Harvard Medical School, Room 10127, One Blackfan Circle, Boston, MA 02115. E-mail address: dale.umetsu{at}childrens.harvard.edu

⁴ Abbreviations used in this paper: AHR, airway hyperreactivity; BAL, bronchoalveolar lavage; -GalCer, -galactosylceramide; i.n., intranasal(ly); FSC, forward scatter; SSC, side scatter; WT, wild type; TARC, thymus and activation-regulated chemokine; MDC, macrophage-derived chemokine; BM, bone marrow.

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