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Invariant NKT Cells Biased for IL-5 Production Act as Crucial Regulators of Inflammation¹

Kaori Sakuishi^*,, Shinji Oki^*, Manabu Araki^*, Steven A. Porcelli, Sachiko Miyake^* and Takashi Yamamura^2,*

^* Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and Department of Microbiology and Immunology and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461

Although invariant NKT (iNKT) cells play a regulatory role in the pathogenesis of autoimmune diseases and allergy, an initial trigger for their regulatory responses remains elusive. In this study, we report that a proportion of human CD4⁺ iNKT cell clones produce enormous amounts of IL-5 and IL-13 when cocultured with CD1d⁺ APC in the presence of IL-2. Such IL-5 bias was never observed when we stimulated the same clones with -galactosylceramide or anti-CD3 Ab. Suboptimal TCR stimulation by plate-bound anti-CD3 Ab was found to mimic the effect of CD1d⁺ APC, indicating the role of TCR signaling for selective induction of IL-5. Interestingly, DNA microarray analysis identified IL-5 and IL-13 as the most highly up-regulated genes, whereas other cytokines produced by iNKT cells, such as IL-4 and IL-10, were not significantly induced. Moreover, iNKT cells from BALB/c mice showed similar IL-5 responses after stimulation with IL-2 ex vivo or in vivo. The iNKT cell subset producing IL-5 and IL-13 could play a major role in the development of allergic disease or asthma and also in the immune regulation of Th1 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 grants from the Ministry of Health, Labour and Welfare of Japan (to T.Y.), the Japan Health Sciences Foundation (to T.Y., S.M., and S.A.P.), and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (to T.Y.).

² Address correspondence and reprint requests to Dr. Takashi Yamamura, Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, 187-8502 Tokyo, Japan. E-mail address: yamamura{at}ncnp.go.jp

³ Abbreviations used in this paper: iNKT, invariant NKT; GC, -galactosylceramide; iGb3, isoglobotrihexosylceramide; HS, healthy subject; MS, multiple sclerosis; DN, double negative; DC, dendritic cell; iDC, immature DC; CBA, cytometric bead array.

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