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Cutting Edge: NKT Cells Constitutively Express IL-23 Receptor and RORt and Rapidly Produce IL-17 upon Receptor Ligation in an IL-6-Independent Fashion¹

Aleksandra V. Rachitskaya^2,*,, Anna M. Hansen^2,*, Reiko Horai^*, Zhuqing Li^*, Rafael Villasmil^*, Dror Luger^*, Robert B. Nussenblatt^* and Rachel R. Caspi^3,*

^* Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892; and Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD 20814

Th17 cells require IL-6 and TGFβ for lineage commitment and IL-23 for maintenance. Unexpectedly, naive IL-6^–/– splenocytes stimulated with anti-CD3 and IL-23 produced normal amounts of IL-17 during the first 24 h of culture. These rapid IL-6-independent IL-17 producers were identified as predominantly DX5⁺ TCRβ⁺ NKT cells, and a comparable response could be found using the invariant NKT-specific ligand -galactosylceramide. Human NKT cells also produced IL-17. NKT cells constitutively expressed IL-23R and RORt. Ligation of either TCR or IL-23R triggered IL-17 production and both together had a synergistic effect, suggesting independent but convergent pathways. IL-17 production was not restricted to a particular subset of NKT cells but they were NK1.1 negative. Importantly, in vivo administration of -galactosylceramide triggered a rapid IL-17 response in the spleen. These data suggest an important biological role for innate IL-17 production by NKT cells that is rapid and precedes the adaptive IL-17 response.

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 National Institutes of Health, National Eye Institute intramural funding.

² A.V.R. and A.M.H. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Rachel R. Caspi, Laboratory of Immunology, National Eye Institute, National Institutes of Health, 10 Center Drive, 10/10N222, Bethesda, MD 20892. E-mail address: rcaspi{at}helix.NIH.gov

⁴ Abbreviations used in this paper: -GalCer, -galactosylceramide; iNKT, invariant NKT; KO, knockout; WT, wild type.