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* Division of Immunology, Children’s Hospital, Harvard Medical School, Boston, MA, 02115;
Department of Pediatric Pneumology and Immunology, University Hospital Charite, Berlin, Germany;
Immunology Program, Stanford University, Stanford, CA 94305; and
Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, and
¶ Department of Pathology, Harvard Medical School, Boston, MA, 02115
The development of airway hyperreactivity (AHR), a cardinal feature of asthma, requires the presence of invariant NKT (iNKT) cells. In a mouse model of asthma, we demonstrated that the induction of AHR required ICOS costimulation of iNKT cells. ICOS was highly expressed on both naive and activated iNKT cells, and expression of ICOS was greater on the CD4+ iNKT than on CD4– iNKT cells. Furthermore, the number of CD4+ iNKT cells was significantly lower in spleens and livers of ICOS–/– and ICOSL–/– mice, and the remaining iNKT cells in ICOS–/– mice were dysfunctional and failed to reconstitute AHR when adoptively transferred into iNKT cell-deficient J
18–/– mice. In addition, direct activation of iNKT cells with -GalCer, which induced AHR in wild-type mice, failed to induce AHR in ICOS–/– mice. The failure of ICOS–/– iNKT cells to induce AHR was due in part to an inability of the ICOS–/– iNKT cells to produce IL-4 and IL-13 on activation. Moreover, survival of wild-type iNKT cells transferred into ICOSL–/– mice was greatly reduced due to the induction of apoptosis. These results indicate that ICOS costimulation plays a major role in induction of AHR by iNKT cells and is required for CD4+ iNKT cell function, homeostasis, and survival in the periphery.
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 the Eleanor and Miles Shore Scholarship for research in Medicine, Harvard Medical School (to O.A.), Children’s Hospital Career Development Grant (to O.A.), National Institutes of Health Grant R01 AI066020 (to O.A.), and National Institutes of Health Grant P01 AI56299 (to G.F., A.H.S., R.D.K., and D.U.) and RO1 HL069507 (to R.D.K.).
2 Address correspondence and reprint requests to Dr. Omid Akbari, Karp Research Laboratories, Childrens Hospital, Harvard Medical School, 1 Blackfan Circle, Boston, MA 02115. E-mail address: omid.akbari{at}childrens.harvard.edu
3 Abbreviations used in this paper: AHR, airway hyperreactivity; iNKT, invariant NK T cell; WT, wild type; DN, double negative; DC, dendritic cell; MC, mononuclear cell; BMDC, bone marrow derived-dendritic cell; RL, airway resistance; Cdyn, dynamic compliance.
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