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Production of Both IL-27 and IFN- after the Treatment with a Ligand for Invariant NK T Cells Is Responsible for the Suppression of Th2 Response and Allergic Inflammation in a Mouse Experimental Asthma Model¹

Hiroyuki Fujita^*,, Annabelle Teng^*, Risa Nozawa^*, Yukiko Takamoto-Matsui^*, Haruka Katagiri-Matsumura^*, Zenro Ikezawa and Yasuyuki Ishii^2,*

^* Laboratory for Vaccine Design, RIKEN Research Center for Allergy and Immunology, Suehiro, Tsurumi, Yokohama, Kanagawa, Japan; and Department of Environmental Immuno-Dermatology, Yokohama City University, Graduate School of Medicine, Fukuura, Kanazawa, Yokohama, Kanagawa, Japan

Using an allergen-induced airway inflammation model, we show that an injection of -galactosylceramide (-GalCer), a ligand for invariant NK T (iNKT) cells, induced IL-27 and that this process is essential for the attenuation of the Th2 response. After the systemic administration of -GalCer into the mice primed with OVA in alum, Th2 cytokine production of OVA-primed CD4⁺ T cells in their lymph nodes, IgG1 and IgE Ab formation, and infiltration of eosinophils in bronchoalveolar lavage after the OVA challenge were suppressed. Systemic administration of rIFN- into OVA-primed mice could not reproduce these effects of -GalCer. IL-27p28 was detected both in the culture supernatant of -GalCer-stimulated spleen cells and in the serum of the -GalCer-treated mice, but not in the iNKT cell-deficient mice. Splenic iNKT cells produced IL-27p28 in the culture supernatant upon stimulation with PMA plus ionomycin, although the transcript of IL-27p28 in the iNKT cells was constitutively expressed regardless of the stimulation. By contrast, the transcript of IL-27EBI3 was induced in the iNKT cells upon stimulation with PMA plus ionomycin in vitro and with -GalCer treatment in vivo, suggesting that IL-27 (p28/EBI3) could be produced by iNKT cells in an activation-dependent manner. Although repeated injections of rIL-27 did not substitute for the effects of a single injection of -GalCer, administration of rIL-27 along with rIFN- reproduced in vivo effects of the -GalCer injection. These data indicate that production of both IL-27 and IFN- by the -GalCer treatment is responsible for suppression of the Th2 response and allergic inflammation.

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 an internal grant from the RIKEN Research Center for Allergy and Immunology.

² Address correspondence and reprint requests to Dr. Yasuyuki Ishii, Laboratory for Vaccine Design, RIKEN Research Center for Allergy and Immunology, 1-7-22, Suehiro, Tsurumi, Yokohama, Kanagawa, Japan 230-0045. E-mail address: ishiiyas{at}rcai.riken.jp

³ Abbreviations used in this paper: iNKT, invariant NK T; AHR, airway hyperreactivity; -GalCer, -galactosylceramide; BAL, bronchoalveolar lavage; DC, dendritic cell; PAS, periodic acid-Schiff; Treg, Regulatory T; rm, recombinant murine.