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An Essential Role for IL-18 in CD8 T Cell-Mediated Suppression of IgE Responses¹

Maria Salagianni^*,, Wong Kok Loon, Matthew J. Thomas, Alistair Noble^* and David M. Kemeny^2,*,

^* Department of Asthma, Allergy, and Respiratory Science, King’s College London School of Medicine, London, United Kingdom; Immunology Center, "Saint Savas" Cancer Hospital, Athens, Greece; Novartis Institutes for Biomedical Research, Horsham, United Kingdom; and Immunology Programme and Department of Microbiology, National University of Singapore, Singapore

The ability of CD8 T cells to suppress IgE responses is well established. Previously, we demonstrated that CD8 T cells inhibit IgE responses via the induction of IL-12, which promotes Th1 and suppresses Th2 responses. In this study, we show that IL-18 also plays an essential role in IgE suppression. In vitro, IL-18 synergized with IL-12 to promote Th1/T cytotoxic 1 and inhibit Th2/T cytotoxic 2 differentiation. OVA-specific TCR transgenic (OT-I) CD8 cells induced both IL-12 and IL-18 when cultured with OVA^257–264 peptide-pulsed dendritic cells. In vivo, IL-18^–/– mice exhibited higher IgE and IgG1 levels compared with wild-type mice after immunization with OVA/alum. Furthermore, adoptive transfer of CD8 T cells from OVA-primed mice suppressed IgE responses in OVA/alum-immunized mice, but not in IL-18^–/– mice. IgE suppression in IL-18^–/– mice was restored if CD8 T cells were coadoptively transferred with IL-18-competent wild-type bone marrow dendritic cell progenitors, demonstrating an essential role of IL-18 in CD8 T cell-mediated suppression of IgE responses. The data suggest that CD8 T cells induce IL-18 production during a cognate interaction with APCs that synergizes with IL-12 to promote immune deviation away from the allergic phenotype. Our data identify IL-18 induction as a potentially useful target in immunotherapy of allergic disease.

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 M.S. was supported by a scholarship from Alexander S. Onassis Public Benefit Foundation (Greek section of Scholarships and Research).

² Address correspondence and reprint requests to Dr. David M. Kemeny, Immunology Programme and Department of Microbiology, Centre for Life Sciences, 28 Medical Drive, National University of Singapore, Singapore 117456. E-mail address: michead{at}nus.edu.sg

³ Abbreviations used in this paper: DC, dendritic cell; BMDCp, bone marrow DC precursor; IRF-1, IFN regulatory factor-1; PCA, passive cutaneous anaphylaxis; Tc1, T cytotoxic 1.